In-situ formed intervertebral fusion device and method

ABSTRACT

An orthopedic device for implanting between adjacent vertebrae comprising: an arcuate balloon and a hardenable material within said balloon. 
     In some embodiments, the balloon has a footprint that substantially corresponds to a perimeter of a vertebral endplate. An inflatable device is inserted through a cannula into an intervertebral space and oriented so that, upon expansion, a natural angle between vertebrae will be at least partially restored. At least one component selected from the group consisting of a load-bearing component and an osteobiologic component is directed into the inflatable device through a fluid communication means.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/448,221, filed on Feb. 14, 2003. The entire teachings of the aboveapplication is incorporated herein by reference.

BACKGROUND OF THE INVENTION

A leading cause of lower back pain arises from lumbar intervertebraldisc pathology, including rupture or degeneration of the disc. Radicularpain in the lower extremities may be caused by the compression of spinalnerve roots by a bulging disc. Additionally, lower back pain may becaused by collapse of the disc and the dysarthrosis of an unstable ordegenerative vertebral facet joint. One proposed method of managingthese problems is to remove the problematic disc and replace it with aporous device that restores disc height and allows for bone growththerethrough for the fusion of the adjacent vertebrae. These devices arecommonly called “fusion devices.”

Intervertebral body fusion devices typically must carry extremely highloads (on the order of 1-4 kN) for a period of several months, or untilfusion occurs. Accordingly, a fusion device or bone graft substitutedesigned for promoting bony fusion at another location in the body (suchas long bone fusion) may not be suitable for use as an intervertebralbody fusion device. For example, many bony fusion devices disclose theuse of a gel such as a hydrogel as the structural carrier for anosteoinductive or an osteogenic component. However, such gels typicallydo not posses the stiffness or mechanical strength found to be requiredfor lumbar intervertebral fusion devices.

In general, delivery of conventional intervertebral fusion devices hasrequired significantly invasive implantation procedures. Open surgicalimplantation of posterior implants requires excision of stabilizingmuscles, ligaments, tendons, and bony structures such as the facetjoints. The implants must not only overcome the destabilization causedby the surgical procedure, but must add the extra stability needed topromote bony fusion. Open anterior surgery in the lumbar spine is veryrisky due to the close proximity of sensitive vascular structures, suchas the aorta and bifurcation of the aorta. Furthermore, the anterioropen procedure can cause significant scar formation on the spine, makinganterior revision surgery, if necessary, even more risky.

Minimally invasive procedures have been developed to help mitigate theseproblems. However, current techniques require appreciable surgicalexpertise and can significantly increase surgery time. Furthermore,insertion of interbody fusion cages through minimally invasive meansoften requires high insertion forces.

A number of such prosthetic implants have been described for serving asan intervertebral disc, or nucleus pulpsus, replacement, involving thedelivery of prosthetic materials through a small diameter cannula nolarger than is needed to perform an adequate discectomy. Therefore, theinjectable prosthetic devices are typically delivered in a first fluidform and then harden to a second form once inside the disc space to spanthe disc space height and preferably fill the disc space followingdiscectomy. However, the requirements for a bone fusion system are verydifferent from those of injectable prosthetic devices.

In summary, there is a need for an intervertebral strut injectable intothe disc space that can create or maintain a preferred spatialrelationship between adjacent vertebral body endplates (curvature anddistraction) and comprises an osteogenic component to promote bonyfusion between the two adjacent vertebra.

SUMMARY OF THE INVENTION

The present invention relates to a device for intervertebral spinalfusion and method of making thereof.

In one embodiment, the present invention is an orthopedic device forimplanting between adjacent vertebrae comprising a generally arcuateballoon and a hardenable material within said balloon.

In another embodiment, the present invention is an intervertebral spinalfusion device comprising at least one arcuate inflatable balloon wherebyat least partially filling the balloon between two adjacent vertebrae atleast partially restores a natural angle between the adjacent vertebrae,and wherein said arcuate balloon contains a load-bearing componentwithin a lumen defined by the balloon.

In another embodiment, the present invention is an intervertebral spinalfusion device comprising a anterior frame having an upper inflatable rimand a lower inflatable rim, and a rigid inflatable posterior frameattached to the upper and lower inflatable rims of the anterior frame.The anterior frame is detachably connected to the first fluidcommunication means. The posterior frame is detachably connected to thesecond fluid communication means. Upon at least partially filling theupper and lower inflatable rims and the posterior frame between twoadjacent vertebrae, a natural angle between said vertebrae is at leastpartially restored.

In another embodiment, the present invention is a method of implantingan intervertebral spinal fusion device, comprising the steps of (a)performing a discectomy while preserving an outer annular shell; (b)inserting an inflatable device that includes a deflated arcuate ballooninto an intervertebral space; (c) directing an osteobiologic componentinto the deflated arcuate balloon in an amount sufficient to inflate theballoon and distract the disc space.

In another embodiment, the present invention is a method of implantingan intervertebral spinal fusion device, comprising the steps of (a)inserting an inflatable device through a cannula into an intervertebralspace, said inflatable device including an arcuate balloon connected toat least one fluid communication means, wherein said inflatable deviceupon expansion between two adjacent vertebrae at least partiallyrestores a natural angle between the adjacent vertebrae; (b) orientingsaid inflatable device so that upon expansion a natural angle betweenvertebrae will be at least partially restored; (c) directing aload-bearing component into the inflatable device through the fluidcommunication means.

In another embodiment, the present invention is a method of at leastpartially restoring a natural angle between two adjacent vertebrae,comprising the steps of (a) inserting an inflatable device through acannula into an intervertebral space; (b) orienting said inflatabledevice so that upon expansion of the device a natural angle betweenvertebrae will be at least partially restored; and (c) expanding saidinflatable device by directing a load-bearing component into saidinflatable device.

In another embodiment, the present invention is a method of deliveringan osteobiologic material comprising (a) inserting an inflatable deviceinto an intervertebral space wherein at least a portion of the deviceupon expansion has a substantially toroidal shape thereby forming anopen cavity defined by an outer surface of the toroidal shape and havingan axial dimension and a radial dimension; (b) orienting at least aportion of the device so that so that the axial dimension of the opencavity is substantially parallel to a major axis of a spinal column of apatient in which the device has been implanted; (b) inflating saidinflatable device by directing a load-bearing component into saidinflatable device; (c) directing an osteobiologic material into the opencavity, said material including at least one water-soluble material; (d)directing an aqueous fluid into the open cavity defined, by the inflateddevice thereby dissolving at least one said water-soluble material, andforming a porous matrix; and (e) delivering additional osteobiologiccomponent into the porous matrix in the amount sufficient to fill atleast 90% of the porous matrix by volume.

In another embodiment, the present invention is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand (a) at least one polymer flowable between 38° C. and 45° C. selectedfrom the group consisting of homopolymers of poly(ε-caprolactone),poly(p-dioxanone), or poly(trimethylene carbonate) or copolymers ormixtures thereof, or copolyesters of p-dioxanone or trimethylenecarbonate and glycolide or lactide or mixtures thereof, and inparticular, copolymers of p-dioxanone/glycolide, p-dioxanone/lactide,trimethylene carbonate/glycolide and trimethylene carbonate/lactide, orcopolyesters of .epsilon.-caprolactone and glycolide or mixturesthereof, or mixtures of homopolymers of ε-caprolactone and lactide; and(b) at least one growth factor resistant to denaturing at at least about45° C. selected from the group consisting of bone morphogeneticproteins.

In another embodiment, the present invention is an intervertebral fusiondevice comprising an in-situ formed osteobiologic component comprising(a) a matrix having an internal surface defining an open porositysuitable for bone growth therethrough, and (b) an osteogenic componentlocated within the open porosity.

In another embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising (a) astrut having a upper surface for bearing against the upper endplate anda lower surface for bearing against the lower endplate, and (b) anin-situ formed osteobiologic component.

In another embodiment the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising a strutcomprising (a) an upper surface for bearing against the upper endplate,(b) a lower surface for bearing against the lower endplate, and (c) aninjectable load bearing composition disposed between the upper and lowersurfaces.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a matrix having an internal surface defining an openporosity suitable for bone growth therethrough, wherein the matrix isformed by a plurality of in-situ bonded beads.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut comprising (a) a first component comprising(i) a lower bearing surface adapted for bearing against a lowervertebral endplate, and (ii) an upper surface comprising a leading end,an angled middle portion and a trailing end; and (b) a second componentcomprising (i) an upper bearing surface adapted for bearing against anupper vertebral endplate and (ii) an upper surface comprising a leadingend, an angled middle portion and a trailing end. The angled portion ofthe first component mates with the angled portion of the secondcomponent.

In another embodiment, the present invention is a kit for providinginterbody fusion across an intervertebral disc space, comprising (a) acannula defining an inner diameter; (b) a hardenable material capable ofsupporting intervertebral load; and (c) a flowable osteobiologiccomposition.

In another embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising (a) astrut having a upper surface for bearing against an upper endplate and alower surface for bearing against a lower endplate, the upper surfaceand lower surface defining a height therebetween, and (b) an in-situformed osteobiologic component. The height of the strut is no greaterthan the height of the disc space.

In another embodiment, the present invention is a method of providinginterbody fusion across an intervertebral disc space, comprising thesteps of (a) providing a cannula defining an inner diameter; (b) movinga load bearing composition through the cannula and into the disc spaceto form a in-situ formed load bearing strut; and (c) moving anosteobiologic composition through the cannula and into the disc space toform an in-situ formed osteobiologic composition.

In another embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising a strutcomprising (a) an upper surface for bearing against the upper endplateand (b) a lower surface for bearing against the lower endplate. Thestrut comprises an in-situ formed load bearing composition.

In another embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising a strutcomprising (a) an upper surface for bearing against the upper endplate,(b) a lower surface for bearing against the lower endplate, and (c) anin-situ formed load bearing composition disposed between the upper andlower surfaces.

In another embodiment the present invention is an intervertebral fusiondevice comprising (a) a strut have a shape memory and comprising (i) anupper surface for bearing against the upper endplate, (ii) a lowersurface for bearing against the lower endplate, and (b) an in-situformed osteobiologic component.

In another embodiment, the present invention is an intervertebral fusiondevice comprising (a) a strut comprising an upper surface for bearingagainst the upper endplate and a lower surface for bearing against thelower endplate, and (b) an in-situ formed osteobiologic componentcomprising a matrix component having an internal surface defining ascaffold having open porosity suitable for bone growth therethrough, andan osteogenic component located within the open porosity.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut comprising an upper surface for bearingagainst the upper endplate and a lower surface for bearing against thelower endplate, and an in-situ formed osteobiologic component comprisingan injectable matrix component, an osteoinductive component embeddedwithin the matrix.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut comprising an upper surface for bearingagainst the upper endplate a lower surface for bearing against the lowerendplate, and an in-situ formed osteobiologic component comprising aninjectable matrix component, and a porogen embedded within the matrix.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut comprising an upper surface for bearingagainst the upper endplate, a lower surface for bearing against thelower endplate, and an in-situ formed osteobiologic component comprisingan expandable device defining a cavity, and an injectable osteobiologiccomposition located within the cavity.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut comprising an expandable device having acavity, an upper surface for bearing against the upper endplate, a lowersurface for bearing against the lower endplate, and an inner walldefining a through hole and an injectable load bearing compositionlocated within the cavity, and an osteobiologic component located in thethroughhole.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut comprising an upper surface for bearingagainst the upper endplate, and a lower surface for bearing against thelower endplate; and an in-situ formed osteobiologic component comprisingan injectable, matrix component essentially free of monomer.

In another embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising a strutcomprising (a) an upper surface for bearing against the upper endplate,(b) a lower surface for bearing against the lower endplate, and (c) anin-situ formed load bearing composition disposed between the upper andlower surfaces and made of a material comprising a cross-linkedresorbable polymer.

The advantages of the present invention are numerous. One advantage isthat the present invention makes possible minimally invasive surgicalprocedures to restore a natural angle and increase disc height betweentwo adjacent vertebrae. Furthermore, the same device used to createdistraction/lordosis can function as the intervertebral implant neededto maintain height and natural angle. Another advantage is that thepresent invention makes possible a minimally invasive procedure tocreate in situ a structural scaffold filled with osteoinductivematerials.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of strength over time of a resorbable polymer and bonegrowth.

FIGS. 2 (a) through 2 (e) are schematic representations of preferredembodiments of a semicircular, circular, bilateral and generallycrescent, arcuate, or toroidal shapes of the device of the presentinvention.

FIGS. 2 (f) and 2 (g) show a perspective and a top view, respectively,of a preferred embodiment of a device of the present invention.

FIG. 3 (a) and FIG. 3 (b) show a perspective and a top view,respectively, of a preferred method of the introduction of a cannulainto the disc space.

FIG. 4 (a) and FIG. 4 (b) show a perspective and a top view,respectively, of a preferred method of the deployment of an inflatabledevice into the disc space through the cannula.

FIG. 5 (a) and FIG. 5 (b) show a perspective and a top view,respectively, of an embodiment of the present invention wherein thedevice comprises a generally toroidal balloon and the osteobiologiccomponent is injected into an open cavity defined by the outer surfaceof the generally toroidal balloon.

FIG. 6 (a) and FIG. 6 (b) show a perspective and a top view,respectively, of an embodiment of the present invention comprising morethan one balloon.

FIG. 7 (a) and FIG. 7 (b) show a perspective and a top view,respectively, of another embodiment of the present invention comprisingmore than one balloon.

FIG. 8 (a) and FIG. 8 (b) show an embodiments of the present inventioncomprising an arcuate inflatable balloon with reinforced walls.

FIGS. 9 (a) through (d) show an embodiment of an inflatable device and amethod of inserting an inflatable device of the present invention intothe disc space, wherein a pair of semi-circular flexible members is usedfor guiding the device.

FIGS. 10 (a) and 10 (b) represent plan and lateral views, respectively,of an embodiment of an inflatable device of the invention whereby a pairof semi-circular flexible upper and lower wall components, which can beused for guiding the device, are joined by an inflatable balloon.

FIGS. 11 (a) and (b) show an embodiment of the present invention whereinthe device comprises four semi-circular flexible components for guidingthe inflatable device into the disc space.

FIGS. 12 (a) and (b) show another embodiment of device of the presentinvention that includes guiding members.

FIGS. 13 (a) through (d) shows a preferred embodiment of the method ofthe present invention. FIG. 13 (a) and FIG. 13 (b) show inserting acannula into an intervertebral space, followed by inserting aninflatable balloon of a generally toroidal shape into an intervertebralspace through the cannula. The balloon is expanded by directing aload-bearing component into said balloon. FIG. 13 (c) shows injecting anosteobiologic component comprising a water-soluble component into anopen cavity, defined by the outer surface of the balloon, and FIG. 13(d) shows dissolving the water-soluble component.

FIGS. 14 (a) and (b) show a top and a lateral view, respectively, ofanother embodiment of a device of the present invention employing aramp.

FIG. 14 (c) is a cross section of the device of FIGS. 14 (a) and (b).

FIG. 14 (d) is a perspective view of the device of FIGS. 14 (a)-(c).

FIG. 15 shows one embodiment of a method of deployment of the device ofFIGS. 14 (a)-(d).

FIG. 16 shows another embodiment of a method of deployment of the deviceof FIGS. 14 (a)-(d).

FIGS. 17 (a) and (b) show a particularly preferred embodiment of thedevice of the present invention in collapsed and expanded configuration,respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a vertebral fusion device forsimultaneously distracting two adjacent vertebral bodies and deliveringa flowable material into a disk space. As used herein, the term“vertebral fusion” refers to a medical procedure that results inmaintaining separation between vertebrae. In one embodiment, vertebralfusion provides for bony ingrowth that fixes two adjacent vertebrae in adesired, for example, distracted and/or angulated, position.

In a preferred embodiment, a natural angle between two adjacentvertebral plates is replicated by fusing the two adjacent vertebrae. Asused herein, the “natural angle” refers either to natural lordosis or tonatural kyphosis. The angle can be positive, negative or zero (i.e.,when the opposing surfaces of the adjacent vertebrae are essentiallycoplanar). In one embodiment, a natural lordosis is replicated orrestored. As used herein, the term “natural lordosis” refers to anatural angle between two adjacent vertebral plates within the lumbar orcervical spine segments wherein the distance between the anteriorportions of the two adjacent vertebral plates is not smaller than thedistance between the posterior portions of the two adjacent vertebralplates. In another embodiment, a natural kyphosis is replicated orrestored. As used herein, the term “natural kyphosis” refers to anatural angle between two adjacent vertebral plates within the thoracicspine segment wherein the distance between the anterior portions of thetwo adjacent vertebral plates is not greater than the distance betweenthe posterior portions of the two adjacent vertebral plates.

In another embodiment of vertebral fusion, a fusion means maintains theseparation between the vertebrae. Preferably, the fusion means at leastpartially restore the natural function of nucleus pulposis by permittingrelative freedom of movement while substantially maintaining theseparation between the vertebrae.

The components of the device comprise at least one member selected fromthe group consisting of a load-bearing component and an osteobiologiccomponent. Preferably, both components are used. In some embodiments,load-bearing component includes osteobiologic component. As used hereinthe term “load-bearing” component or material refers to any materialcapable of supporting vertebrae in distracted position. The load-bearingcomponent can include a hardenable material or a noncompressible fluidcontained within an inflatable balloon. The terms “strut” refers to anypart, portion or component of the device, including a flowable material,that either alone or in combination with other parts, portions orcomponents of the device is capable of supporting vertebrae indistracted position. Examples of a strut include a hardened flowablematerial, a balloon with rigid walls and an inflatable balloon or bagfilled with a hardenable material or a noncompressible fluid. Thepurpose of the strut is to bear the high spinal loads. In addition, thestrut can be used to increase the disc space height and/or at leastpartially restore or create natural curvature of the spinal region beingfused. Increasing disc height is often critical for decompressing nerveroots and restoring or creating healthy spine curvature is important forpreventing accelerated degeneration of adjacent intervertebral discs.The term “arcuate” refers to a shape having curvature roughlycorresponding to the perimeter of a vertebral endplate, but does notinclude enclosed rings or generally annular structures.

As used herein, the “osteobiologic” component or material refers to anymaterial that can induce and/or support existing or new bone growth. Insome embodiments, the load-bearing material includes osteobiologicmaterial. For example, a material comprising bone growth factors ormesynchemal stem cells is an osteobiologic component. Osteobiologiccomponent can further include either one or both an osteoinductivecomponent and an osteoconductive component. As used herein, the“osteoinductive” component or material refers to any material that caninduce bone growth. Preferably, osteoinductive components includessignal molecules required to induce the osteoprogenitor cells to formnew bone. Examples of osteoinductive components are bone morphogeneticproteins (BMP's), growth differentiation factors (GDF's) andtransforming growth factors (TGF). As used herein, the “osteoconductive”component or material refers to any material that can provide supportfor bone growth subsequent to induction. Examples of osteoconductivecomponents include natural collagen-based materials including bone, andsynthetic porous resorbable polymers and ceramics.

Generally, the present invention relates to in situ formedintervertebral fusion devices. Preferably, the components of the in situformed device can be delivered percutaneously (e.g., through a cannulahaving a diameter of no more than 5 mm, preferably no more than 2 mm).However, the precursor components of the in-situ formed device can alsobe delivered in cannulae of much larger dimension (such as up to 18 mm,or through a Craig needle). More preferably, the components of thein-situ formed device are delivered into the disc space in the form ofinjectable compositions.

For the purposes of the present invention, the term “in situ formed”refers to any material that is delivered into the disc space in a firstform and takes on a different form after placed in the disc space. Insome embodiments, “in situ formation” includes delivering a viscousfluid into the disc space and hardening that fluid. In some embodiments,“in situ formation” includes delivering discrete components into thedisc space and bonding (preferably, heat bonding or by reaction)together those components. In some embodiments, “in situ formation”includes delivering discrete components into an opening in an inflatabledevice located in the disc space and preventing their escape from theinflatable device by closing off the opening of the inflatable device.In some embodiments, “in situ formation” includes delivering discretecomponents into the disc space and assembling together those componentswithin the disc space.

In situ formation” excludes simply packing particles such as autograftor allograft particles into the disc space, as well as simply deliveringa gel into the disc space.

Without being limited to any particular theory, it is believed that inconventional fusion systems, there is often a race between implantdegradation and bone growth. Now referring to FIG. 1, the hypotheticalstrength profiles of a conventional resorbable implant (dotted line) andof the bone that replaces the implant (solid line) are provided. For thepurpose of explaining FIG. 1, the strength of the system is defined asthe lesser of the strength of the resorbable implant and the strength ofthe healing bone. It then follows that between the time of the surgicalprocedure (T₀) and the time for complete bone healing to take place(T_(F)), the load applied to the system must never be above the strengthof the system at point C (shown as S_(C)). It is known in the art thatthe maximum in vivo average daily living load on the human lumbar spineis approximately 4,000 N. Assuming that this is the maximum load to beexperienced by the system, then the system strength should not fallbelow 4,000 N.

Because the strut can be made relatively strong (e.g., capable ofsupporting about 15 kN in axial compression), even when the load appliedto the system is relatively high, the strength of the system will stillbe sufficient to support the disc space and fusion will occur. Oncesufficient bone growth through the osteobiologic component occurs, thestrut may degrade without endangering support of the disc space.

To summarize, the strut supports the disc space while the osteobiologiccomposition grows bone.

In preferred embodiments, the strut of the present invention acts in amanner similar to the cortical rim of a vertebral body. Desirablefeatures for the load bearing composition of the strut are as follows:

-   -   a) sufficient strength to bear the typical loads borne by        vertebral bodies;    -   b) stiffness similar to that of cortical bone (or, in relatively        thick embodiments, cortico-cancellous bone);    -   c) degradation resistance (e.g., capable of bearing at least 15        MPa, preferably at least 25 MPa) for at least one year,        preferably at least 18 months;    -   d) resorbability.

Accordingly, in one embodiment, the present invention is anintervertebral spinal fusion device comprising a resorbable load-bearingmaterial wherein the combination of the resorbable load-bearing materialand the new bone growth provides a load-carrying capacity that is atleast sufficient to support spinal load. Preferably, the load-bearingmaterial includes or is supplemented by an osteobiologic component. Inanother embodiment, the present invention is a method of making anintervertebral fusion device comprising selecting a resorbableload-bearing material wherein the combination of the resorbableload-bearing material and the new bone growth provides a load-carryingcapacity that is at least sufficient to support spinal load.

In one embodiment, the strut should have a size sufficient to provide afootprint covering between about 3% and about 40% of the area of thecorresponding vertebral endplate. Preferably, the strut foot coversbetween about 10% and about 30%, more preferably between about 10% andabout 20% of the corresponding vertebral endplate.

In some embodiments, in which the osteobiologic component contains atleast one of a) a growth factor and b) an osteogenic component, e.g. asource of cells (such as stem cells), it is believed that the strutfootprint can be in the range of about 10% to about 20% of the discspace. This is because it is believed that these additives sufficientlyshorten the time to fusion so that the danger of strut subsidence issufficiently low. Similarly, in some embodiments, in which theosteobiologic component contains both a) a growth factor and b) stemcells, it is believed that the strut footprint can be in the range ofabout 5% to about 10% of the disc space.

It is further believed that providing the osteobiologic component withboth a) a growth factor and b) stem cells provides further desirabledesign options. These additives may also reduce or eliminate the needfor posterior or supplemental fixation. Currently posterior fixation isgenerally thought to be highly desirable to achieve a fusion success inthe interbody space. In some embodiments, the provision of effectiveamounts of such additives can increase the speed for fusion so as torender superfluous the posterior or supplemental fixation, and patientswould no longer need to endure a more invasive pedicle screw procedureto apply the stability needed for fusion.

In some embodiments, the device can comprise a balloon of semicircular,circular, bilateral (comprising more than one balloon) and generallytoroidal shape. Preferred embodiments and positions of a device of thepresent invention on an endplate 8 of a vertebra 10 are shown in FIGS. 2(a) through (e). Now referring to FIG. 2 (a), this shape allows theballoon 12 to essentially cover at least the anterior periphery 14 ofthe corresponding vertebral endplate 8, and thereby bear a substantialportion of the spinal load. This shape further allows the surgeon tofirst place the device in place and then fill the remaining portion ofthe disc space with, for example, an osteobiologic component.

In other embodiments, as in FIG. 2 (b), the balloon 12 has aquasi-circular shape. This device has the advantage of providing evenmore of a load-bearing footprint than the embodiment of FIG. 2 (a), andalso substantially prevents unwanted leakage of the osetobiologiccomponent during subsequent filling of an open cavity defined by anouter surface of the balloon.

Now referring to FIG. 2 (c), in some embodiments, the device comprisestwo balloons 12 that can be used to support the vertebral load. The useof two balloons allows a surgeon to evenly support the load on each sideof the endplate 8.

Now referring to FIG. 2 (d), in some embodiments, the balloon 12 has agenerally toroidal (“banana”) shape. The banana shape allows the surgeonto put in place a single device preferably on the anterior half 14 ofthe disc space. In other embodiments, the strut has the footprint of abanana cage such as that described in Attorney Docket #DEP 5012, “NovelBanana Cage”, filed Dec. 31, 2002, U.S. Ser. No. 10/334,599, thespecification of which is incorporated by reference in its entirety.

Now referring to FIG. 2 (e), in some embodiments, the strut 12 isintroduced translaterally so as to form a single ramp stretchingessentially transversely across the endplate 8. This design inadvantageous when used in a posterolateral approach of surgery, as thisapproach takes advantage of the fact that the muscle planes in thevicinity of the approach allow the implant to be delivered in a lessinvasive manner.

Now referring to FIG. 2 (f), in a preferred embodiment, the device 12 ofthe present invention has a substantially semiannular footprint. Thedevice 12 is placed on the anterior portion of the endplate 8 of avertebra 10 so that height D of a anterior portion of the device isequal or greater than height h of a posterior portion of the device 12.Referring to FIG. 2 (g), the device 12 defines an internal radius r_(i),an external radius r_(e) and thickness t. In one embodiment, illustratedin FIG. 2 (g), r_(i) is approximately about 22 mm, r_(e) isapproximately about 25 mm and t is approximately about 3 mm.

In preferred embodiments, the height of the strut is at least 90%, andpreferably at least equal to, the height of the natural disc space. Thisallows the surgeon to distract the disc space and restore at least aportion of the disc height. In some embodiments, the height of the strutis greater than that of the natural disc space.

As used herein the word “distraction” will refer to the separation ofjoint surfaces to a desired extent, without rupture of their bindingligaments and without displacement. Distraction can be accomplished byany suitable means, for example mechanical or hydrostatic means.Mechanical means can include, for instance, attaching hooks or jacks tothe bony endplates and using those hooks or jacks to separate the bones.Optionally, the surgeon can employ external traction. In one embodiment,an in-situ foaming material is used as a distraction device. Other meansinclude, for example, hydrostatic means, e.g., by pressurized injectionof the biomaterial itself. By the use of distraction, the disc space canbe sufficiently re-established to achieve any desired final dimensionsand position. Optionally, and preferably, the means used to accomplishdistraction also serves the purpose of forming one or more barriers(e.g., balloons) for the flowable load bearing strut material.

The disc space can be distracted prior to and/or during either adiscectomy itself and/or delivery of a flowable biomaterial. Aconstricted disc space is generally on the order of 3 to 4 mm in height.Suitable distraction means are capable of providing on the order ofabout 3 atmospheres to about 4 atmospheres, (or on the order of about 40psi to about 60 psi) in order to distract that space to on the order of8 to 12 mm in height.

In one embodiments, the strut has a wedged shape so that the height ofthe anterior portion of the expanded device is greater than the heightof the posterior portion of the expanded device. This allows the surgeonto restore lordosis when the interbody fusion device is used in eitherthe lumbar or cervical regions of the spine. Preferably, the wedgedshape produces an angle of between 5 and 20 degrees, more preferablybetween 5 and 15 degrees.

In another embodiment, the strut has a wedged shape so that the heightof the anterior portion of the expanded device is smaller than theheight of the posterior portion of the expanded device. This allows thesurgeon to restore kyphosis when the interbody fusion device is used inthoracic regions of the spine. Preferably, the wedged shape produces anangle of between 5 and 20 degrees, more preferably between 5 and 15degrees.

In preferred embodiments, the height of the medial portion of the strutis greater than the height of the lateral portion of the expandeddevice. This geometry more closely mimics the natural doming of the discspace.

With the injectable device of the present invention, there is provided a“custom” implant formed to the anatomy of the patient's endplates. Theprovision of a conformable implant may provide a faster and moreconsistent fusion.

In some embodiments, the annulus fibrosus can itself serve as a suitablemold for the delivery and solidification of either the flowableload-bearing material (in one embodiment) or the osteobiologic component(in another embodiment). Free injection may optimize the extent to whichthe injectable device conforms to the contour of the disc space, therebyenhancing resistance to retropulsion. Optionally, the interior surfaceof the annulus fibrosus can be treated or covered with a suitablematerial in order to enhance its integrity and use as a mold.

In some embodiments, at least one of the flowable materials is deliveredinto an inflatable device (such as a balloon) previously placed in thedisc space.

In some embodiments, the load bearing composition is delivered into aninflatable device (such as a balloon) previously placed in the discspace. Now referring to FIGS. 3 (a) and (b), in one preferred method, acannula 18, having an inner diameter of no more than 6 mm, is insertedinto the disc space. Next, and now referring to FIGS. 4 (a) and (b), theinflatable device 12 is deployed through the exit opening of the cannula18 and the flowable load bearing composition is introduced into theinflatable device at a pressure and volume suitable to expand theinflatable device and distract the disc space.

The fixed shape of the expanded device allows the surgeon topredetermine the shape of the flowable material and simply fill thedevice with the flowable material. The device substantially preventsunwanted flow of the material. The prevention of unwanted flow desirablyprevents the material from damaging important surrounding structuressuch as the spinal cord, aorta and vena cava. Also, the inflatabledevice can be tailored to fill any portion of the disc space.

Further, the present inventors believe that inclusion of an inflatableballoon in a strut can assure that the opposing trends of degradation ofbioabsorbable materials and new bone growth will result in fusion of thevertebrae in a position approximating the natural angle between twoadjacent vertebrae. If the balloon is made of a resorbable,water-impermeable material, the balloon will effectively shield theload-bearing composition from water during the initial stages of fusionand so delay the onset of hydrolysis and degradation of the load-bearingmaterial. Preferably, the balloon begins to degrade within about 1-2months after fusion of the osteobiologic composition, thereby allowingthe load-bearing material it contains to slowly degrade and grow bone.

In some preferred embodiments, the distraction of the disc space isaccomplished by an inflatable, yet rigid, balloon or bladder. Theballoon can be delivered in deflated form to the interior of the annulusand there inflated in order to distract the disc space and provide aregion for the delivery of biomaterial. The balloon is preferably ofsufficient strength and of suitable dimensions to distract the space toa desired extent and to maintain the space in distracted position for aperiod of time sufficient for the biomaterial to be delivered and,optionally, to harden.

One of the primary functions of the balloon is to influence or controlthe shape of the hardenable material, following injection therein. Theimplantable balloon is not normally required to restrain pressure overan extended period of time. Thus, a greater design flexibility may bepermitted, as compared to conventional angioplasty or other dilatationballoons. For example, the balloon may be porous, either for drugdelivery as has been discussed, or to permit osteoincorporation and/orbony ingrowth.

In one particularly preferred embodiment, there is provided a method forfusing an intervertebral disc space, comprising the steps of:

-   -   a) using microsurgical techniques to perform a discectomy while        preserving an outer annular shell;    -   b) inserting a deflated balloon into the disc space;    -   c) injecting a flowable load bearing composition into the        deflated balloon (preferably, in an amount sufficient to        distract the disc space), and    -   d) solidifying the flowable strut material.

In one particularly preferred embodiment, there is provided a method forfusing an intervertebral disc space, comprising the steps of:

-   -   a) using microsurgical techniques to perform a discectomy while        preserving an outer annular shell,    -   b) inserting a deflated balloon having peripheral struts into        the disc space,    -   c) injecting an osteobiologic component into the deflated        balloon in an amount sufficient to inflate the balloon and        distract the disc space with the strut component of the balloon.

Optionally, and preferably, the space is distracted by the use of one ormore suitable insertable or inflatable devices, e.g., in the form ofinflatable balloons. When inflated, such balloons provide rigid walls(e.g., fiber supported) that are sufficiently strong to distract thespace. An inflatable device providing sufficient strength and dimensionscan be prepared using conventional materials. In one embodiment, theuninflated balloon can be delivered to the center of the annular shell,and there inflated to expand the annular shell and in turn, distract thespace. In another embodiment, the uninflated balloon can be delivered tothe anterior rim of the annular shell, and there inflated to provide acavity for the injection of the load bearing flowable material.Preferably, the load bearing composition is injected in an amountsufficient to distract the space.

The inflatable device can be delivered to the disc space by any suitablemeans, e.g., in deflated form retained within or upon the end of a rigidor semi-rigid rod. Once positioned within the disc, either centrallywithin the annular shell or along the annular rim, a suitable gas (e.g.,nitrogen or carbon dioxide) or the flowable load-bearing material can bedelivered through the rod in order to inflate the balloon in situ, in asubstantially radial or longitudinal direction. In some embodiments,beads of the load bearing strut material are simply packed into theballoon. The fact that the balloon is properly placed can be confirmedby the use of ancillary means, such as using a C-arm, or byself-effecting means embodied within the balloon itself or its deliveryapparatus.

In terms of its component parts, in one preferred balloon deliverysystem of the present invention there is provided an inflatable device,a motor drive unit, with a remote controller, associated tube sets, anonscope inflow delivery cannula having independent fluid dynamicspressure and flow rate adjustments, attachments for the flush, vacuum,waste canister, and overflow jars.

Suitable materials for preparing balloons of the present invention mayinclude those that are presently used for such purposes as balloonangioplasty. Suitable materials provide an optimal combination of suchproperties as compliance, biostability and biocompatibility, andmechanical characteristics such as elasticity and strength. Balloons canbe provided in any suitable form, including those having a plurality oflayers and those having a plurality of compartments when expanded. Auseful balloon apparatus will include the balloon itself, together witha delivery catheter (optionally having a plurality of lumen extendinglongitudinally therewith), and fluid or gas pressure means.

Examples of suitable materials (e.g., resins) for making balloonsinclude, but are not limited to, polyolefin copolymers, polyethylene,polycarbonate, polyethylene terephthalate and ether-ketone polymers suchas poly(etheretherketone). Such polymeric materials can be used ineither unsupported form, or in supported form, e.g., by the integrationof Dacron™ or other fibers. Preferably, the materials of construction ofthe balloon are resistant to softening or melting at a temperature of atleast 80° C., preferably at least 100° C., more preferably at least 250°C. In addition, the balloon (or balloon-like structure) may be made outof any of a wide variety of woven or nonwoven fibers, fabrics, metalmesh such as woven or braided wires, and carbon. Biocompatible fabricsor sheet material such as ePTFE and Dacron™ may also be used.

Balloons can also take several forms, depending on the manner in whichthe biomaterial is to be delivered and cured. A single, thin walledballoon can be used, for instance, to contact and form a barrier alongthe interior surface of the remaining annular material. Once positioned,the flowable load bearing component can be delivered and solidifiedwithin the balloon to serve as a load bearing strut of the presentinvention. In such an embodiment, the balloon is preferably of a typethat will allow it to remain in position, without undue detrimentaleffect, between the annular material and the solidified load-bearingcomponent.

Optionally, a balloon can be provided that fills essentially only thecentral portion of the disc space. In such an embodiment, the ballooncan be, for instance, in the shape of a cylinder. Such a balloon can beprovided such that its upper and lower walls can be positioned tocontact the opposing vertebral bodies, and its side walls will providesufficient strength to cause, distraction of the space upon inflation.Thereafter, the load-bearing component is delivered to the perimeter ofthe annular space, i.e., the space between the annular material and theballoon, and there solidified. Optionally, the balloon can be graduallydeflated as additional biomaterial is inserted into the space. Then,once the load bearing material is stably positioned, the osteobiologiccomponent is introduced into the balloon, thereby filling the balloon.

In some embodiments, the balloon has metallic wires or other imagablemeans incorporated into it. Any material that can be seen underfluoroscopy would be acceptable. Potential materials include any metal,metal alloys, or ceramics that could be combined with a polymer. Thematerial can be in the form of wires, a mesh, or particles incorporatedinto the balloon or on its surface.

In some embodiments, the balloon has an inner surface that is chemicallyactive so as to bond with the balloon filler as it polymerizes. As usedherein, a chemical “bond” is said to exist between two atoms or groupsof atoms when the forces acting between them are strong enough to leadto the formation of an aggregate with sufficient stability to beregarded as an independent species. As used herein, “chemically active”means capable of forming a chemical bond. In one example, the surface ischemically modified by means such as plasma polymerization. In thiscase, the balloon is placed in a vacuum chamber and plasma containing asmall molecule (an amine for example) is created. The balloon surface isbombarded by the small molecule and the small molecule is chemicallyattached to its surface. The balloon's surface with its amine groups canthen react with the polymer that is injected into the balloon (i.e., anepoxy), forming a device that would have greater fatigue propertiessince the “composite” of balloon and balloon filler are chemicallybonded to one another.

The desired quantities of the load-bearing and osteobiologic componentsof the present invention are delivered by minimally invasive means tothe prepared site. Prior to delivery, these components can be stored insuitable storage containers, e.g., sterile, teflon-lined metalcanisters. The flowable components can be delivered, as with a pump,from a storage canister to the delivery cannula on demand. Thecomponents can be delivered in the form of a single composition, or canbe delivered in the form of a plurality of components or ingredients.

In some embodiments, the inflatable device can be filled with a viscousmaterial that later solidifies to form the strut or osteobiologiccomponent. The viscous material can be a heated polymer (such as acomposition containing polycaprolactone), or polymer precursorcomponents (such as the photopolymerizable anhydrides disclosed by A. K.Burkoth, Biomaterials (2000) 21:2395-2404, the entire teachings of whichare incorporated herein by reference).

In some embodiments, a flowable load bearing composition, such aspolycaprolactone, heated to a temperature yielding a viscosity in therange of from about 100 to about 500 cps is injected into the balloonunder pressure such as by using a pump and pressure within the range offrom about 4 ATM to about 10 ATM or more depending upon viscosity,balloon strength and other design considerations. The pump is run for asufficient duration and under a sufficient pressure to ensure that thepolycaprolactone wets all of the p-dioxanone fibers. This may range fromabout 10 minutes or more to about an hour, and, in one application wherethe pump was run at about 5 ATM pressure, requires at least about 1hour. Specific method parameters may be optimized depending upon theviscosity of the polycaprolactone, infusion pressure, infusion flowrate, density of the packed fibers, and other variables as will beapparent to those of skill in the art in view of the disclosure herein.

It has been reported in the literature that balloons inserted into thedisc space may be subject to retropulsion. Therefore, in someembodiments of the present invention, upon expansion, the inflatabledevice forms an upper surface having a first plurality of teethprojecting outwards from the upper surface. Upon expansion of thedevice, these teeth will project in the direction of the upper endplateand, upon complete expansion of the device, will engage the endplate tofrom a secure interlock with the endplate and resist retropulsion.

Preferably, the teeth are made of a stiff resorbable material, such aspolyetheretherketone (PEEK). Preferably, the teeth have a height ofbetween 0.5 and 1.5 mm, and have a triangular cross-section.

In some embodiments of the present invention, upon expansion, theinflatable device forms an upper surface formed of a material having ahigh coefficient of friction. Upon expansion of the device, the highcoefficient of friction of the upper and lower surfaces will case a dragupon any movement of the upper surface and therefore keep the device inplace and resist retropulsion.

Preferably, the upper and lower surfaces of the inflatable device aremade from a material selected from a group consisting of polyether blockcopolymer (PEBAX), ABS (acrylonitrile butadiene styrene); ANS(acrylonitrile styrene); Delrin®; PVC (polyvinyl chloride); PEN(polyethylene napthalate); PBT (polybutylene terephthalate);polycarbonate; PEI (polyetherimide); PES (polyether sulfone); PET(polyethylene terephthalate); PETG (polyethylene terephthalate glycol),high and medium melt temperature: polyamides, aromatic polyamides,polyethers, polyesters, Hytrell®, polymethylmethacrylate, polyurethanes:copolymers, EVA (ethylene vinyl acetate) or ethylene vinyl alcohol; low,linear low, medium and high density polyethylenes, latex rubbers, FEP,TFE, PFA, polypropylenes, polyolefins; polysiloxanes, liquid crystalpolymers, inomers, Surlins, silicone rubbers, SAN (styreneacrylonitrile), nylons: 6, 6/6, 6/66, 6/9, 6/10, 6/12, 11, all PEBAXs12; polyether block amides; thermoplastic elastomers and the like.

In some embodiments, the vertebral endplates opposing the disc space areroughened. The roughening provides hills and valleys into which aflowable polymer can flow and harden, thereby forming a mechanicalinterlock between the device and the bony surface and resistingretropulsion.

The roughening can be provided mechanically (as with a curette), orchemically (as by an acid), or by an energy-transmitting device (as withan ablation unit preferably assisted with hyperconductive fluid, such ashypertonic saline).

In some embodiments, the flowable polymer forming a mechanical interlockcan be a separate layer. In others, the flowable polymer can be acomponent of the strut. In others, the flowable polymer can be acomponent of the osteobiologic composition.

In some embodiments, the strut portion of the device can have an outerlayer of a scaffold material appropriately seeded with osteogenicfactors and/or growth factors to produce quick bone ingrowth, therebyeffectively locking the strut in place.

In some embodiments, an outer layer of a scaffold material appropriatelyseeded with osteogenic factors and/or growth factors can also be appliedto a balloon component of the osteobiologic component. The seeding againproduces quick bone ingrowth, thereby effectively locking theosteobiologic component in place.

Balloons of the present invention can be made using materials andmanufacturing techniques used for balloon angioplasty devices. U.S. Pat.No. 5,807,327 by Green, the entire teachings of which are incorporatedherein by reference, (hereinafter “Green”) discloses balloons that maybe used in the present invention. The materials disclosed by Green forthe formation of the balloon include tough non-compliant layer materials(col. 8, lines 18-36) and high coefficient of friction layer materials(col. 8, lines 42-54).

Now referring to FIGS. 5 (a) and (b), in some embodiments, theload-bearing component is delivered into the disc space through aninflatable balloon 12, and the osteobiologic component 20 is freelyinjected. This embodiment is desirable because the balloon 12 can act asa barrier to hydrolysis of the load-bearing component, therebyincreasing the longevity of the load-bearing component. In contrast, theabsence of the balloon covering the osteobiologic component may bedesirable in instances in which it is desirable to immediately begin thebone growth process.

This embodiment may also be desirable in instances in which theload-bearing component comprises a cross-linkable composition, and thesurgeon desires to provide a barrier between the patient's tissue andthe precursors during the reaction of the precursors.

Now referring to FIGS. 6 (a) and (b), in some embodiments, both the loadbearing and the osteobiologic components are delivered into the discspace using a device comprising two separate inflatable balloons 12.This embodiment is desirable in instances in which both the annulusfibrosis has been functionally breached, and there is a concern thatflowable materials would flow from the disc space and through the breachand into the remainder of the body. In this embodiment, it is preferredthat the balloon containing the osteobiologic material be at leastsemi-permeable to nutrients and preferably resorbable. As used herein,the term “semipermeable” refers to a material that is non-permeable tothe flowable materials described above yet permeable to important waterand nutrients to support bone growth therein. Suitable semi-permeablematerials include both porous and non-porous polymeric constructs suchas films, fabrics (woven and non-woven) and foams.

In some embodiments, both the load bearing and the osteobiologiccomponents are delivered into the disc space through the same inflatabledevice.

Now referring to FIGS. 7 (a) and (b), another embodiment of the deviceand method of the present invention is shown wherein the devicecomprises at least two inflatable balloons 12. In this embodiment, theload-bearing component is delivered into the disc space through at leasttwo inflatable balloons 12 and the osteobiologic component 20 is freelyinjected into the disk space using the space between the balloons.

In some embodiments, the osteobiologic component is delivered into thedisc space through an inflatable device, and the load-bearing componentis freely injected. This embodiment may be desirable in instances inwhich the osteobiologic component comprises an in situ hardenablecomposition such as a calcium containing cement, or a crosslinkablepolymer such as polypropylene fumarate), polyanhydride, or polyoxaester,and the surgeon desires to cordon off the patient from the precursorsduring their reaction. In this embodiment, it is further preferred thatthe balloon containing the osteobiologic material be at leastsemi-permeable to nutrients and preferably resorbable. This embodimentmay also be desirable in instances in which the load-bearing compositioncomprises growth factors and the surgeon desires to immediately beginthe bone growth process in the load-bearing component.

In some embodiments, the load-bearing component is delivered into thedisc space through an inflatable device, and the osteobiologic componentis freely injected. This embodiment may also be desirable in instancesin which the annulus fibrosis in essentially intact and the surgeondesires to immediately begin the bone growth process in the load-bearingcomponent.

In some embodiments, the inflatable device comprises a single peripheralwall having an upper and lower surface, upper and lower walls, and acavity formed therebetween. For the purposes of the present invention,this shape of this embodiment is referred to as a “puck”. The peripheralwall and upper and lower walls of the puck could be designed so as to bepercutaneously deliverable through a cannula having an inside diameterof between 0.5 and 18 mm, preferably no more than 4 mm.

In one embodiment, the peripheral wall of the puck is designed to beload bearing when the inflatable device is disposed in its inflatedposition. Preferably, the peripheral wall is made of a shape-memorymetal, such as Nitinol, or a thin film alloy.

In some embodiments, the periphery of the balloon is reinforced withfibers. In some embodiments thereof, the peripheral wall comprisespolymer fibers. These fibers can be made into a weave that issufficiently flexible (in the longitudinal direction of the fiber) topass through the cannula and expand into the expanded state. Typically,these fibers have high tensile strengths so that they can veryefficiently accommodate the problematic hoop stresses that may betransferred from the osteobiologic component contained within the middleannulus of the balloon.

Various patterns of reinforcement of the peripheral side-walls with thefibers are contemplated. In one embodiment, the fibers form X-shapedcross-hatching pattern. In another embodiment, the fibers form acontinuous wave-like pattern having peaks and troughs, where said peaksand troughs approach upper and lower surfaces.

In one embodiment, the walls of the device are reinforced by an internalframe forming a polygonal structure having sides on the upper, lower andperipheral surfaces.

In some embodiments, the peripheral reinforcement is made of aresorbable polymer fiber.

The upper and lower walls of this puck embodiment are designed toinitially accept and contain the osteobiologic component that is flowedinto the puck cavity. Accordingly, the upper and lower walls should beat least semi-permeable so as to contain the osteobiologic component. Inpreferred embodiments, the upper and lower walls are made of aresorbable material that quickly resorbs, thereby exposing the containedosteobiologic material to blood flowing from the decorticated endplates.

In some embodiments, this absorbable material has an elastomericquality. This elastomeric quality allows the resorbable upper and lowerwalls to be delivered through the cannula, and flatten upon deviceexpansion. In preferred embodiments, this elastomeric polymer isselected from the materials disclosed in U.S. Pat. No. 6,113,624 byBezwada, the entire teachings of which are incorporated herein byreference (hereinafter “Bezwada”). In other embodiments, this absorbablematerial is not elastomeric, and is preferably made of a thin film metalalloy or a braided metal alloy.

Now referring to FIGS. 8 (a) and 8 (b) there is provided a device 30 ofthe present invention comprising an inflatable portion 32 that includesan arcuate inflatable balloon.

Now referring to FIG. 8 (a), in its pre-deployed state, the inflatableportion 32 of the device 30 is conveniently repeatedly folded uponitself, thereby decreasing the size of the device 30 and allowing forminimally invasive insertion into the disc space. During insertion intothe disc space, the device 30 is preferably inserted in the sandwichorientation as shown in FIG. 8 (a) wherein the structural walls 34 aredisposed essentially parallel to the vertebral endplates. The sandwichorientation allows height H of the structural walls 34 to meet or exceedthe disc space height, while the folded width W does not exceed the discspace height.

Now referring to FIG. 8 (b), after insertion into the disc space, fluidis flown into the inflatable portion 32 of the device 30, therebyexpanding the device 30 into the configuration as shown. The height H ofthe structural walls 34 is sufficient to restore the natural height ofthe disc space. After the device 30 distracts the disc space, thecavity, formed by the expanded portion 32, is filled by an osteobiologiccomponent.

The structural walls 34 of this embodiment are preferably attached tothe inflatable portion 32 by an adhesive. The structural walls 34 shouldbe designed so that the width W and the strength and modulus of thematerial of construction allow for both support of the disc space andbony fusion through the osteobiologic component.

In some embodiments, the height H of the structural wall 34 is at leastequal to the height of the natural disc space. This condition desirablyrestores the height of the disc space when the inflatable portion 32 isexpanded. In some embodiments, the height H of the anterior portion ofthe wall 34 is greater than the height h of the posterior portion of thewall 34. This condition desirably provides a lordotic effect uponexpansion of the inflatable portion 32.

In some embodiments, the walls 34 are made of allograft bone, andpreferably comprise cortical bone. In others, the walls are made of asynthetic resorbable polymeric material. In some embodiments, the wallsmay be sufficiently porous to provide an effective scaffold, therebyallowing bony fusion therethrough.

In some embodiments, the wall component 34 of this embodiment is made ofbone graft. In alternative embodiments, component 34 comprisesadditional inflatable portions. After insertion into the disc space, aload bearing composition may be flowed into the cavities of theseadditional inflatable portions, thereby expanding these additionalinflatable portions and eventually producing the desired dimensions ofthe walls 34.

In some embodiments, each wall 34 is translaterally oriented in theexpanded device. In this condition, a first wall supports essentiallythe anterior portion of the opposing cortical rims, while the secondwall supports essentially the posterior portion of the opposing corticalrims, so that one of these walls will essentially bear the entire loadduring flexion and the other wall will bear essentially the entire loadduring extension. Preferably, these walls have a length L correspondingto the anterior and posterior aspects of the cortical rim.

The inflatable portion 32 has upper and lower surfaces 36 and 38 forcontacting the adjacent vertebral endplates, a peripheral side surface40 connecting the upper and lower surfaces 36 and 38, and an opening 42in the peripheral side surface 40. Upon a flow of fluid through theopening 42 from a cannula 18, the inflatable portion 32 is expanded andsurfaces 36, 38 and 40 are pushed apart sufficiently to form an internalcavity suitable for containing an osteobiologic component. Because theosteobiologic component retained within this cavity is preferably atleast semipermeable in order to provide bony fusion, the upper and lowersurfaces 36 and 38 of the inflatable portion 32 preferably do not act asbarriers to bony fusion. Accordingly, it is preferred that the upper andlower surfaces 36 and 38 are either porous (preferably, semipermeable)or quickly resorbable. Preferably, the upper and lower surfaces 36 and38 are made of a material that resorbs within 7 days, preferably 3 days,preferably one day. Examples of fast-resorbing materials includedenatured collagen, polysaccharide-based materials such as starch andoxidized regenerated cellulose, and hydroxylated lactide-glycolidecopolymers. In some embodiments, the opening in the side surface 40 isformed closely adjacent to the structural wall 34, positioned anteriorlyon a vertebral endplate.

In some embodiments, the inflatable device 30 of this embodiment has aconfiguration designed to match the geometry of the disc space, and isselected from the group consisting of an anterior lumbar interbodyfusion (ALIF) configuration, a posterior lumbar interbody fusion (PLIF)configuration, a vertebral body replacement (VBR) configuration, and ananterior cervical discectomy and fusion (ACDF) configuration.

By reducing the effective size of the device 30, this embodiment of thepresent invention desirably minimizes the access window required forinsertion of intervertebral devices. By providing anatomicallyappropriate structural walls 34, the device 30 provides a stableenvironment for the musculoskeletal growth factors to develop.

Now referring to FIGS. 9 (a) and (b), one embodiment of an inflatabledevice of the present invention is shown. The device 60 comprises anouter side-wall component 62, an inner side-wall component 64, and aballoon 66 disposed between and attached to said inner and outer wallcomponents. The short cranial-caudal height of the inner and outer wallsallows for the device to be inserted into the disc space without havingto distract the disc space prior to insertion. Subsequent filling of theballoon with an in-situ hardenable, load-bearing material causes theballoon to expand beyond the cranial and caudal margins of thesidewalls, thus providing the necessary distraction of the disc space.Furthermore, the sidewalls prevent expansion of the balloon such thatthe thickness of the device is minimized upon inflation. Minimized wallthickness is important for ensuring maximum area for bone growth(fusion) between the adjacent vertebrae. In some embodiments, thefootprints of the outer and inner side-wall components 62 and 64represent substantially equal arcs of two concentric circumferences.This allows placing device 60 along the periphery of the anteriorportion 14 of a vertebral endplate 8 and filling a cavity therewithinwith a load bearing material.

In some embodiments of device 60, the outer and inner walls 62 and 64are made of a flexible plastic such as poly(ethyleneterephthalate), asuperelastic metal such as Nitinol, or a flexible material/geometrycombination, whereby each wall can be deformed into a relativelyelongated shape for delivery to the disc space through a cannula 18. Thesidewalls are sufficiently rigid to guide the device into the desiredlocation in the disc space but sufficiently flexible to allow deliverythrough the cannula. Referring to FIG. 9 (c), during the insertion ofthe device 60, upon release from the cannula 18, components 62 and 64can then take on the desired arcuate shape. Referring to FIG. 9 (d),subsequent to insertion, the device 60 is expanded by injecting aload-bearing component, an osteobiologic component or a combinationthereof into a cavity formed by the components 62, 64, and 66. Anysuitable injection means can be used, for example, a syringe pump 70.

The above characteristics of components 62 and 64 ensure that the cavityproduced between side walls 62, 64 can be filled so that the device 60distracts the disc space and can also create a wedge shape for creatingor restoring healthy curvature of the spine.

An alternative embodiment of inflatable device of the present inventionis shown in FIGS. 10 (a) and (b). Device 260 comprises an upper wallcomponent 266 and a lower wall component 268 joined by an inflatableballoon 270. In some embodiments, the footprints of the upper and lowerwall components 266 and 268 represent substantially equal arcs of twoconcentric circumferences. This allows placing device 260 along theperiphery of the anterior portion 14 of a vertebral endplate 8 andfilling a cavity therewithin with a load bearing material.

In some embodiments of device 260, the upper and lower wall components266 and 268 are made of a superelastic material such as Nitinol, or aflexible material/geometry combination, whereby each wall can bedeformed into a relatively elongated shape for delivery to the discspace through a cannula 18. Operationally, device 260 is similar todevice 60. Insertion of device 260 can be accomplished in a mannerdepicted in FIG. 9 (c). Upon release from cannula 18, components 266 and268 can then take on the desired arcuate shape. Subsequent to insertion,device 260 is inflated by injecting a load-bearing component, anosteobiologic component or a combination thereof into balloon 270. Anysuitable injection means can be used, for example a syringe pump.

Preferably, balloon 270 is semi-permeable. In preferred embodiments,balloon 270 is made of a material that quickly resorbs, thereby exposingthe contained osteobiologic material to blood flowing from thedecorticated endplates.

Generally, the strut is deliverable through a cannula having an insidediameter of between 3 mm and 18 mm, preferably between 4 mm and 12 mm,more preferably between 5 mm and 10 mm.

In some embodiments in which the surgeon desires to minimize the size ofthe incision, the strut is preferably deliverable through a cannulahaving an inside diameter of between 0.5 mm and 6 mm, preferably between1 mm and 4 mm, more preferably between 2 mm and 3 mm.

Preferably, the upper and lower surfaces of the upper and lower walls,respectively, have teeth that prevent excessive movement of the strutafter implantation.

Now referring to FIGS. 11 (a) and (b), the device 80 comprises four railcomponents 82 wherein the footprints of the rail components 82 representsubstantially equal arcs of two concentric circumferences. Components 82are joined by an inflatable balloon 84 such that the device can beinserted in a collapsed configuration as shown in FIG. 11 (b) and thenexpanded as shown in FIG. 11( a) once filled with a load-bearingmaterial to increase disc height and provide thickness for load bearingsupport.

In one embodiment of the present invention, device 80 is shown in FIGS.12 (a) and (b). In this embodiment, device 80 is delivered in agenerally diamond-shaped configuration, shown in plan view on FIG. 12(a) and in lateral view in FIG. 12 (b). In this embodiment, the upperand lower rails 82 will cause slight subsidence of the vertebral bodyendplates, thus providing stability of the implanted device.

Now referring to FIGS. 13 (a) through (d) a preferred embodiment of themethod of the present invention is shown. As shown in FIGS. 13 (a) and13 (b), a cannula 18 is inserted into an intervertebral space. Next aninflatable balloon 12 of a generally toroidal shape is inserted throughthe cannula 18 into the intervertebral space. The balloon 12 is expandedby directing a load-bearing component into said balloon. Referring toFIG. 13 (c), subsequent to balloon expansion, osteobiologic component 20is injected into the open cavity defined by the outer surface of theballoon 12. Preferably, the osteobiologic component comprises awater-soluble component. Next, the water-soluble component is dissolved,thus forming a porous matrix shown in FIG. 13 (d).

In one embodiment of the present invention the load-bearing component isdelivered through a balloon, and the osteogenic component is provided ina hydrogel phase of the osteobiologic component. Examples of suitablehydrogels are provided hereinbelow.

In other embodiments, solid components of the strut are inserted intothe body percutaneously and assembled in situ to form the strut. In somein situ embodiments, the strut is formed by bonding together twobondable components. Preferably, the bondable materials are selectedfrom the group consisting of heat bondable materials such aspolycaprolactone, and polymerizable materials such as polypropylenefumarate) and polyoxaesters including photo-curable materials such aspolyanhydrides.

In other embodiments, load-bearing materials in the form of beads isdelivered into the inflatable device and packed into the device so as tocreate a stable strut having an open interstitial porosity. In someembodiments, the beads may be packed without subsequent stabilizationother than closing off the opening of the balloon. In these embodiments,the beads are preferably polyarylether ketone (PAEK), more preferablypolyetherether ketone (PEEK) with chopped carbon fiber.

In some embodiments, a bonding material may be subsequently flowed intothe interstitial porosity to further stabilize the packed beads.Preferably, this bonding material comprises an aliphatic polyester suchas polycaprolactone (PCL). The bonding material may be resorbable andmay include osteogenic additives such as growth factors and stem cells.

In some bead embodiments of the device, the beads of the load-bearingmaterial are made of a heat-bondable material, such as polycaprolactone.When the beads are so constituted, heat may be delivered into thepacking and soften the contacting surfaces of the beads. Upon subsequentcool down to body temperature, the contacting surfaces solidify tofurther stabilize the packed structure. In some embodiments, the heat isprovided exogenously. In other embodiments, the heat is provided by thepatient's body heat (˜37° C.).

Now referring to FIGS. 14 (a)-(d), another embodiment of the device ofthe present invention 300 comprises at least two bondable components 310and 320, that are delivered into the disc space in unassembled form,placed closely adjacent one another, and then bonded together,preferably by heat bonding.

Referring to FIG. 14 (b), representing a lateral view of the device ofFIG. 14 (a) as seen in the direction of arrow A, and to FIG. 14 (d),representing a perspective view of device 300, in one embodiment, device300 comprises first and second portions 310 and 320. First portion 310has a lower bearing wall 312, upper angled wall 314, and a leading wall316 and a trailing wall 318. Second portion 320 has an upper bearingwall 322, lower angled wall 324 and a leading wall 326 and a trailingwall 328. The combined height of the assembled portion H exceeds that ofthe disc space. The angled walls form the same angle so that the leadingedge of the second portion can be ramped up the angled wall of the firstportion.

In use, the first portion 310 is placed in the disc space. Because theheight of the first portion is less than the disc space, the firstportion 310 is easily positionable anywhere within the disc space. Next,the second portion 320 is introduced into the disc space and ramped upthe angled wall of the first portion. Corresponding rails and groove areprovided on the angled walls of the first and second portion so as toguide the second portion along the anlong wall of the first portion (seebelow). Because the second portion only contacts the lower portions ofthe first portion, the upper wall 322 of the second portion 320 does nottouch the adjacent endplate during ramping and so the ramping is easy.Only when the ramping is essentially complete does the upper wall of thesecond portion contact the adjacent upper endplate. Preferably, theoverall height of the ramp H is slightly greater than that of the discspace, so that distraction is achieved when the leading edge of thesecond portion reaches the leading edge of the first portion.

Referring to FIG. 14 (c), in one embodiment, a cross-section of thedevice of FIG. 14 (a) is shown, taken along arrows B. As shown in FIG.14 (c), angled wall 314 of first portion 310 includes a grove 330, whileangled wall 324 of second portion 320 includes a ridge 332, designed tofit into a slide against grove 330. In some embodiments, ridge 332further includes a metal filament 334.

It is understood that the locations of grove 330 and ridge 332 can beinterchanged to between angled walls 314 and 324 of upper and lowerportions 310 and 320.

Preferably, the rail and groove feature of the ramps has a Morse taperso as to lock the ramp in its assembled form when the leading edge ofthe second portion reaches the leading edge of the first portion.

Once the two ramp portions are in place, an electric current or heat ispassed through wire that passes through the length of the rail of thefirst portion. The resulting localized heating of the contacting areassoftens this region without changing the dimensions of the ramp. Uponcooling, a highly stable, heat bonded ramp results.

Because the ramp of this embodiment is not flowed into the disc space,and the heating is very localized, extremely strong, high temperaturematerials such as PEEK may be used as the material of construction. Insome embodiments, the ramp is made of a high temperature resorbablematerial. In some embodiments, the high temperature absorbable materialis amorphous and has a glass transition temperature of above 100° C.Preferably, the amorphous absorbable is PLA. In some embodiments, thehigh temperature absorbable material is crystalline and has a meltingpoint of above 100° C. Preferably, the crystalline absorbable isp-dioxanone.

In some ramp embodiments, a guidewire is guided through the center ofthe ramp guide. The guidewire would allow the ramps to be inserted overthe guidewire. The guidewire could be remotely steered into place viaIGS or equivalent, and then the ramps could be passed over the guidewireinto place. The ramps could be semi-rigid which would allow them tofollow the guidewire through the soft tissue, over the wire.

In other ramp embodiments, an “I”-Beam ramp cage is provided. The rampcage discussed above could incorporate or mate with modular tops andbottoms. These tops and bottoms would have tracks, which would locate onguides fixed to the ramps (or the guides could be on the modular top,and tracks on the ramps) which would aid insertion and ensure the rampswere connected to these modular tops and bottoms. The surfaces of themodular tops and bottoms would go between the ramps and the vertebralbodies such that when assembled, a cross-section of the ramp/top/bottomassembly would resemble an “I”-Beam. This would allow for thinner rampsto ease insertion via an MIS technique or equivalent, and the modulartops and bottoms would provide sufficient surface area to preventsubsidence of the implant into the vertebral bodies. The ramps andmodular tops could be shaped in several configurations, insertedassembled, or assembled within the disk space.

In other embodiments, there is provided a ribbon-shaped ramp having alongitudinal through-hole. A threaded rod is inserted through the middleof the ribbon so that, as the threaded rod is turned, the ribbon would“accordion” itself, increasing its height within the disk space. This“accordion”-ing could be achieved by other methods, such as a spring, acable, etc.

Now referring to FIG. 15, one embodiment of a method of use of device300 shown in FIGS. 14 (a)-(d) is depicted. In this embodiment, the firstand second ramp portions 310 and 320 are introduced translaterally so asto form a single ramp stretching essentially transversely across thedisc space. This design in advantageous when used in a posterolateralapproach, as this approach takes advantage of the fact that the muscleplanes in the vicinity of the approach allow the implant to be deliveredin a less invasive manner. In some embodiments thereof, the medialportion of the ramp has a height that is higher than the lateralportions. This feature provides the doming that is advantageous ininterbody fusions

Now referring to FIG. 16, another embodiment of a method of use ofdevice 300, shown in FIGS. 14 (a)-(c) is depicted. In this embodiment,the ramp of the present invention may be advantageously used in a PLIFprocedure. In particular, two ramps may be constructed in-situ so as toform bilateral struts similar to the Steffee struts.

Therefore, in accordance with the present invention, there is providedan intervertebral fusion device comprising a strut comprising:

a) a first component comprising:

-   -   i) a lower bearing surface adapted for bearing against a lower        vertebral endplate, and,    -   ii) an upper surface comprising a leading end, an angled middle        portion and a trailing end; and

b) a second component comprising:

-   -   i) an upper bearing surface adapted for bearing against an upper        vertebral endplate, and,    -   ii) an upper surface comprising a leading end, an angled middle        portion and a trailing end,    -   wherein the angled portion of the first component mates with the        angled portion of the second component.

In some embodiments of the present invention, the struts are completelydense. This feature maximizes the strength of the strut, and so isdesirable for the load bearing. In other embodiments, the strut hasopenings sized to permit bony fusion therethrough. In some embodiments,the upper and lower walls have openings designed to promote bony fusionfrom the upper endplate to the lower endplate. In other embodiments, thesidewalls of the strut also have such openings. In some embodiments, theopenings have a diameter of at least 2 mm. In other embodiments, theopenings are in the range of from 50-500 um, more preferably between 100and 300 urn, preferably between 100 and 250 um. These preferred openingsizes are believed to be more conductive to bone growth.

Materials and Compositions Suitable for Use in the Invention

Provided below is a listing of various attributes of the load bearingcomposition and osteobiologic component of the present invention:

Typical Typical Load Bearing Load Bearing Osteobiologic OsteobiologicFeature Application Application Application Application Resorptionof >12 months, 12-24 months 1-3 months 2 months Matrix preferablybeginning >12 months Overall High >50 MPa Moderate 1-5 MPa StrengthOverall Cortico- 0.1-2 GPa Cancellous 0.1-0.5 GPa Compression cancellousBone Modulus Bone Second Phase Reinforcement fibers Osteoconductive NanoHA particles Aqueous phase No no Yes Alginate Osteogenic No no Yes MSCscomponent Growth factors Yes BMP Yes BMP Footprint Support of disc 5-40areal % Bony fusion 60-95 areal % space volume

As used herein, the term “second phase” refers to an additive thatenhances the performance of the material, for example carbon fibersenhance the strength of the material and calcium phosphate particulatesenhance the osteoconductivity of the material. As used herein, the term“aqueous phase” refers to a component of the material capable ofmaintaining cell viability, e.g. an alginate hydrogel.

Examples of load-bearing components that satisfy the above Table includeat least one compound selected from the group consisting of poly(lacticacid), poly(glycolic acid), p-dioxanone fibers, polyarylethyl,polymethylmethacrylate, polyurethane, amino-acid-derived polycarbonate,polycaprolactone, aliphatic polyesters, calcium phosphate, unsaturatedlinear polyesters, vinyl pyrrolidone and polypropylene fumaratediacrylate or mixtures thereof.

Examples of osteobiologic components that satisfy the above Tableinclude at least one member selected from the group consisting ofmesenchymal stem cells, a growth factor, cancellous bone chips,hydroxyapatite, tri-calcium phosphate, polylactic acid, polyglycolicacid, polygalactic acid, polycaprolactone, polyethylene oxide,polypropylene oxide, polysulfone, polyethylene, polypropylene,hyaluronic acid, bioglass, gelatin, collagen and a polymeric fiber.

Because the overall mechanical properties of the load bearing andosteobiologic components can be significantly varied by the inclusion orexclusion of additives such as fibers, particles, cross-linking agentsand aqueous phases, some matrix components may be used in some instancesas the matrix for the load bearing component and in other instances asthe matrix for the osteobiologic component. For example,polycaprolactone may be used in conjunction with p-dioxanone reinforcingfibers as a matrix for a load bearing component, and may also be used inconjunction with polylactic acid and hydroxyapatite as a matrix for anosteobiologic component.

For the purposes of the present invention, the term “hardenable” refersto a material that can be delivered through a cannula into the discspace in a viscous form. In one embodiment, material that can bedelivered through a cannula, having at least about 6 mm internaldiameter. In another embodiment, a cannula has a diameter of no morethan about 6 mm.

Generally, the flowable load-bearing composition and osteobiologiccomponent of the present invention are flowable, meaning they are ofsufficient viscosity to allow their delivery through a cannula of on theorder of about 2 mm to about 6 mm inner diameter, and preferably ofabout 3 mm to about 5 mm inner diameter. Such biomaterials are alsohardenable, meaning that they can solidify, in situ, at the tissue site,in order to retain a desired position and configuration.

In some instances, the hardenable material is simply a material (such asa low temperature polymer) having a melting point (for crystallinematerials) or a glass transition temperature (for amorphous materials)less than 100° C., and is solid a body temperature (37° C.). In someembodiments, these low temperature materials are simply heated to thepoint where they are viscous and flowable and then injected into thedisc space. The subsequent cooling of the viscous material to bodytemperature then solidifies them. Because these materials do not need toreact in-situ, they are desirable for their relative inertness.Accordingly, in some embodiments, they may be freely injected into thedisc space without a protective balloon.

In some instances, the hardenable material comprises a cross-linkablecomponent (or “cross-linking agent”). These materials are desirablebecause cross-linking enhances the strength of the resulting material.Accordingly, in some embodiments, the load-bearing component comprises across-linking agent. In such embodiments, it is desirable that thecross-linking agent be delivered into the disc space through a balloonso that the balloon may protect the surrounding tissue from the reactivecomponents during the reaction.

In some embodiments, the load-bearing component comprises across-linking agent. In some embodiments, the osteobiologic componentcomprises a cross-linking agent.

In some embodiments, the hardenable material comprises a polymer and across-link agent. In some embodiments, the hardenable material mayfurther comprise a monomer. In some embodiments, the hardenable materialmay further comprise an initiator. In some embodiments, the hardenablematerial may further comprise an accelerant.

Preferably, the cross-linking component is made from a two-partcomposition comprising a monomer and a crosslinking agent.

In some embodiments, the cross-linked composition is flowable at atemperature of between 37° C. and 40° C.

In preferred embodiments, the cross-linkable component is resorbable.For the purposes of the present invention, a resorbable material loses50% of its initial strength within no more than two years afterimplantation.

Providing a resorbable cross-linkable component is desirable because itnot only provides the high initial strength required for supporting thedisc space in an intervertebral fusion application, but also allows forthe eventual replacement by bone fusion.

In some preferred embodiments, the resorbable cross-linkable componentcomprises those cross-linkable components disclosed by Wise in U.S. Pat.No. 6,071,982, the entire teachings of which are incorporated herein byreference.

In preferred embodiments, the cross-linkable component is UV curable.Examples of UV curable cross-linkable components are disclosed inBiomaterials (2000), 21:2395-2404 and by Shastri in U.S. Pat. No.5,837,752, the entire teachings of which are incorporated herein byreference.

In some embodiments, the cross-linkable component is water-curable. Insuch instances, the resulting body is typically somewhat weak, and so itis preferred that the water-curable cross-linkable compound be used as amatrix for the osteobiologic component.

In some embodiments, the strut is made of a non-resorbable material.Since the non-resorbable material does not degrade over time, the use ofthe non-resorbable material provides the surgeon with a measure ofsafety and prevents collapse of the disc space in the event theosetobiologic composition does not produce a fusion.

Preferably, the non-resorbable material is a polymer. The selection of apolymer allows the material to be flowed into place.

In some embodiments, the load bearing polymer is a polyarylethyl ketone(PAEK). More preferably, the PAEK is selected from the group consistingof polyetherether ketone PEEK, polyether ketone ketone PEKK andpolyether ketone PEK. In preferred embodiments, the PAEK ispolyetherether ketone.

In general, although they possess high strength, PAEK-type polymers havea very high melting point (e.g., 250° C.) and so are not amenable toflow at desirable temperatures. Accordingly, embodiments of the presentinvention using PAEK as the load bearing composition would typicallydeliver PAEK in a solid form, such as in bead form or as pre-constructedcomponents, and then assemble and heat bond the components in the discspace under very high temperatures (e.g., 250° C.). These hightemperatures would likely require the use of a highly insulated expandeddevice.

In some embodiments, the strut is a composite comprising fiber,preferably carbon fiber. Composite struts comprising carbon fiber areadvantageous in that they typically have a strength and stiffness thatis superior to neat polymer materials such as a polyarylethyl ketonePAEK.

In some embodiments, the fiber, preferably, carbon fiber, comprisesbetween 1 percent by volume and 60 percent by volume (vol %). Morepreferably, the fiber comprises between 10 vol % and 50 vol % of thecomposite. In some embodiments, the polymer and carbon fibers arehomogeneously mixed. In others, the composite strut is a laminate. Insome embodiments, the carbon fiber is present as chopped state.Preferably, the chopped carbon fibers have a median length of between 1mm and 12 mm, more preferably between 4.5 mm and 7.5 mm. In someembodiments, the carbon fiber is present as continuous strands.

In especially preferred embodiments, the composite strut comprises:

-   a) about 40% to about 99% (more preferably, about 60% to about 80    vol %) polyarylethyl ketone PAEK, and-   b) about 1% to about 60% (more preferably, about 20 vol % to about    40 vol %) carbon fiber,    wherein the polyarylethyl ketone PAEK is selected from the group    consisting of polyetherether ketone PEEK, polyether ketone ketone    PEKK and polyether ketone PEK.

In some embodiments, the composite strut consists essentially of PAEKand carbon fiber. More preferably, the composite strut comprises about60 wt % to about 80 wt % PAEK and about 20 wt % to about 40 wt % carbonfiber. Still more preferably the composite strut comprises about 65 wt %to about 75 wt % PAEK and about 25 wt % to about 35 wt % carbon fiber.

In the context of an arc-shaped inflatable container, for use as acontainer for the load bearing composition of the present invention, thephysical requirements of the flowable load bearing component will dependupon the length and diameter of the arc as well as the physicalrequirements imposed by the implantation site. For certain embodiments,certain load-bearing compositions may or may not exhibit sufficientphysical properties. Physical properties of the load bearing componentscan also be modified through the addition of any of a variety ofreinforcements, such as carbon fibers, Kevlar™ or Titanium Rods, wovenor laser etched metallic tubular stents, or other strength enhancers aswill be understood in the art.

Certain composite materials, such as carbon fibers embedded in a bondingagent such as a polycaprolactone are believed to be particularly usefulin forming the load bearing component of the present invention. Forexample, graphite (carbon fibers) having a diameter within the range offrom about 0.003 to about 0.007 inches is provided in bundles (tows)composed of from about 3,000 to about 12,000 fibers. One typical fiberuseful for this purpose is manufactured by Hexcel Carbon Fibers, SaltLake City, Utah, Part No. HS/CP-5000/IM7-GP 12K. Preferably, the Towtensile strength is in the range of from about 5,000 to about 7,000 Mpa.Tow tensile modulus is within the range of from about 250 to about 350Gpa. Within the range of from about 30 to about 60 bundles of the carbonfiber described above is packed in a deflated balloon, optionally alongwith a Ni—Ti stent having an 8 mm diameter and 8 cm length. Although anyof a variety of stents may be utilized, one useful structure is similarto the Smart Stent (Cordis), and it helps keep the structure intact andalso adds structural strength to the implanted structure.

In an alternate embodiment, carbon fibers having within the range offrom about 15 to about 45 degrees of braids are utilized within theinflatable device to reinforce the load bearing material. The braid maybe in the form of a plain weave, and may be obtained, for example, fromComposite Structures Technology (Tehachapi, Calif.). A 0.5 inch diameterof 45 degrees braided carbon fiber sleeve is positioned within thecenter of the balloon. This braided sleeve conforms dimensionally to theinside diameter of the balloon. A 0.3 inch diameter braided carbonsleeve may also be positioned concentrically within the balloon, withinthe outer braided carbon fiber sleeve. Unidirectional fibers arethereafter introduced inside of the ID of the inner braided carbonsleeve. Unidirectional fibers are also introduced into the annular gapbetween the two braided sleeves. The volume of the fiber per volume ofballoon is generally within the range of from about 40% to about 55%.After placement of the foregoing structure within the portals of thescrews, the flowable load bearing material of the present inventionhaving a viscosity within the range of from about 100 cps to about 500cps is injected under 10 atmospheres pressure into the balloon. The useof braided sleeves will produce higher structural resistance to sheerstress as a result of torsional loads, plus the ability to distributeunidirectional fibers in a homogenous manner within the balloon at alltimes.

In some embodiments, the polymer comprises polymethylmethacrylate(PMMA). In preferred embodiments, the matrix comprises a radio-opaqueagent. A blend of diurethane dimethacrylate (DUDMA) and triethyleneglycol dimethacrylate (TEGDMA) that is suitable for the load bearingstrut is disclosed in WO 03/005937, the entire teachings of which areincorporated herein by reference.

In some embodiments, the load bearing composition comprisespolyurethane. In some embodiments, the polyurethane materials disclosedin U.S. Pat. No. 6,306,177 by Felt (hereinafter “Felt”), thespecification of which is incorporated by reference to the extent it isnot inconsistent with the remainder of the specification, is selected.

Polyurethanes can be tailored to have optimal stiffness by adjusting theratio of soft segment to hard segment ratio in the polymer. Furthermore,polyurethanes can be prepared as two-part systems that will cure uponmixing. Preferred polyurethanes, e.g., thermoplastic polyurethanes(“TPU”), are typically prepared using three reactants: an isocyanate, along-chain macrodiol, and a short-chain diol extender. The isocyanateand long-chain diol form a “soft” segment, while the isocyanate andshort-chain diol form a “hard” segment. The hard segments form ordereddomains held together by hydrogen bonding. These domains act ascross-links to the linear chains, making the material similar to across-linked rubber. It is the interaction of soft and hard segmentsthat determines and provides the polymer with rubber-like properties.

In some embodiments, the strut comprises a photocurable material. Insome photocurable embodiments, the material comprises organophosphorouscompounds. These compounds are advantageous because the resultingproduct is calcium phosphate based, and so is both biocompatible andresorbable.

In some embodiments the strut has a resorbable matrix material. Aresorbable matrix material is desirable because it is eventuallyresorbed by the body, and may eventually be replaced by bone.

In some embodiments, the resorbable strut is a high temperaturematerial. For the purposes of the present invention, a high temperaturematerial flows above 100° C. In these cases, the high temperatureabsorbable material enters the disc space as a plurality of componentsin a solid form. The components are then contacted in the disc space,and heat is applied to bond the components without deforming theassembled shape.

In some embodiments, the load bearing composition includes a matrixcomprising an amino-acid derived polycarbonate.

In some embodiments, the osteobiologic component comprises a matrixcomprising a biodegradable polyurethane.

In some embodiments, the osteobiologic component comprises a matrixcomprising an amorphous polymer and has a glass transition temperatureof below 100° C. Preferably, the amorphous absorbable is D,L-polylacticacid (PLA).

In general, little modification of polylactic acid polymers is possiblebecause there are no other functional groups on the side chain, exceptthe methyl of the lactic acid residue. One possibility to modify theproperties of these polymers is to form copolymers with residues havingmore diverse side chain structures, e.g., lysine.

A poly(lactide-co-lysine) functionalized with peptide containing thearginine-glycine-aspartate (RGD) sequence was prepared by removal of thebenzyoxycarbonyl protecting group on the lysyl residue and peptidecoupling. The peptide concentration was found to be approximately 3.1mmol/g, which could be translated into a peptide surface density of 310fmol/cm². A surface density of as low as 1 fmol/cm² of an RGD peptidehas been previously determined to promote cell adhesion to an otherwisenonadherent surface (Massia and Hubbell, 1991). Therefore, by carefullyprocessing the copolymer, biodegradable films with cell adheringproperties can be prepared from the copolymer of lactide and lysine.

Other strategies have also been employed to widen the properties ofpolylactides. For example, polylactic acid (PLA) has also beensynthesized as an acrylic macromonomer and subsequently copolymerizedwith polar acrylic monomers (e.g., 2-hydroxyethylmethacrylate) (Barakatet al., 1996). These polymers were studied as amphiphilic graftcopolymers for drug delivery purposes. The surface properties of thesepolymers may be controlled by the ratio of the polylactic acid graftlength and copolymer content, and can be potentially used to control thedrug release profile and biodistribution. Other examples of thisapproach include grafting polylactic acid blocks to geraniol andpregnenolone (Kricheldorf and Kreiser-Saunders, 1996).

In some embodiments, the high temperature resorbable material issemi-crystalline and has a melting point of above 100° C. Preferably,the semi-crystalline absorbable is selected from the group consisting ofp-dioxanone, L-polylactic acid and poly(glycolic acid) (PGA), andmixtures thereof.

In some embodiments, the strut comprises at last 90 wt % of an aliphaticpolyester. Preferably, the aliphatic polyester is polycaprolactone(“PCL”).

Polycaprolactone (PCL) is a linear polyester formed through the ringopening of the monomer epsilon-caprolactone. Polycaprolactone is asemi-crystalline thermoplastic resin, which can be readily molded atmoderate temperatures to yield tough translucent products. Itscrystalline melting point is about 60° C., which represents atheoretical upper temperature limit of use for the present invention.Above its melting point the material is characterized by a high degreeof conformability and workability.

Other polymers such as poly(dodecene-1) and transpolyisoprene are alsouseful in this invention. These polymers are characterized by beingcrystalline at room temperature, non-crystalline at about 70° C. andhaving a relatively rapid rate of crystallization when cooled to bodytemperature. These polymers do not crystallize like simple compounds sothat there is a reasonable time lag after the polymer reaches bodytemperature before crystallization is complete. This permits sufficienttime for the flowable composition to be positioned in the disc spacewhile the polymer is still pliable.

In some embodiments, there is provided an absorbable componentcomprising a polymer formed from aliphatic lactone monomers selectedfrom the group consisting of p-dioxanone, trimethylene carbonate,ε-caprolactone, glycolide, lactide (l, d, dl, meso),delta-valerolactone, beta-butyrolactone, epsilon-decalactone,2,5-diketomorpholine, pivalolactone, alpha, alpha-diethylpropiolactone,ethylene carbonate, ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione,3,3-diethyl-1,4-dioxan-2,5-dione, gamma-butyrolactone,1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 1,4-dioxan-2-one,6,8-dioxabicycloctane-7-one, and combinations thereof.

In one preferred embodiment, the strut comprises a load bearingcomposition consisting essentially of polycaprolactone. According toWalsh, Biomaterials (2001), 22:1205-1212, the compressive strength ofessentially solid polycaprolactone is about 15 MPa, and its compressivemodulus is about 0.5 GPa.

In general, the higher molecular weight polycaprolactones (PCLs) arepreferred, as they tend to have a higher strength and degrade moreslowly. Preferably, the molecular weight of the polycaprolactone is atleast 30,000 Daltons. More preferably, the molecular weight of thepolycaprolactone is at least 40,000 Daltons.

In one preferred embodiment, the strut comprises a load bearingcomposition of cross-linked polycaprolactone. The cross-linking of thepolycaprolactone should enhance its strength. More preferably, the loadbearing composition comprises a self-interpenetrating network (S-IPN)comprising a network of host polycaprolactone and cross-linkedpolycaprolactone. According to Hao, Biomaterials (2003), 24:1531-39, theentire teachings of which are incorporated herein by reference, certainmechanical properties of polycaprolactone increased by about 3 fold whenit was formed as a S-IPN. When at least 15 wt % HAP was added, thetensile modulus increased to 6 fold over conventional polycaprolactone.If the 3 fold increase in certain mechanical properties reported by Haowould also be realized in compressive strength and compressive modulus,then, the compressive strength of the S-IPN of polycaprolactone may beabout 45 MPa, and its compressive modulus may be about 1.5 GPa.

In some embodiments, the polycaprolactone is heat treated to enhance itscrystallinity, and thereby even further enhance its resistance todegradation.

In yet a further aspect of the present invention, the above describedpolymers of the present invention may be liquid or low meltingtemperature, low molecular weight polymers, with or without photocurablegroups. The liquid or low melting polymers are of sufficiently lowmolecular weight, having an inherent viscosity of about 0.05 to about0.5 dL/g, to yield materials which can easily flow, with or without heatbeing applied, through a small diameter delivery device such as asyringe or cannula, with or without mechanical assistance, a caulkinggun, a soft-sided tube, and the like.

The aliphatic polyesters useful in the practice of the present inventionwill typically be synthesized by conventional techniques usingconventional processes. For example, in a ring opening polymerization,the lactone monomers are polymerized in the presence of anorganometallic catalyst and an initiator at elevated temperatures. Theorganometallic catalyst is preferably tin based, e.g., stannous octoate,and is present in the monomer mixture at a molar ratio of monomer tocatalyst ranging from about 10,000/1 to about 100,000/1. The initiatoris typically an alkanol, a glycol, a hydroxyacid, or an amine, and ispresent in the monomer mixture at a molar ratio of monomer to initiatorranging from about 100/1 to about 5000/1. The polymerization istypically carried out at a temperature range from about 80° C. to about220° C., preferably from about 160° C. to about 200° C., until thedesired molecular weight and viscosity are achieved.

Under the above described conditions, the homopolymers and copolymers ofaliphatic polyesters, will typically have a weight average molecularweight of about 5,000 grams per mole to about 200,000 grams per mole,and more preferably about 10,000 grams per mole to about 100,000 gramsper mole. Polymers of these molecular weights exhibit inherentviscosities between about 0.05 to about 3.0 deciliters per gram (dL/g),and more preferably about 0.1 to about 2.5 dL/g as measured in a 0.1g/dL solution of hexafluoroisopropanol (HFIP) or chloroform at 25° C.

Suitable lactone monomers used in the matrices of the present inventionmay be selected from the group consisting of glycolide, lactide (l, d,dl, meso), p-dioxanone, trimethylene carbonate, ε-caprolactone,delta-valerolactone, beta-butyrolactone, epsilon-decalactone,2,5-diketomorpholine, pivalolactone, alpha, alpha-diethylpropiolactone,ethylene carbonate, ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione,3,3-diethyl-1,4-dioxan-2,5-dione, gamma-butyrolactone,1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 1,4-dioxan-2-one,6,8-dioxabicycloctane-7-one and combinations of two or more thereof.Preferred lactone monomers are selected from the group consisting ofglycolide, lactide, p-dioxanone, trimethylene carbonate andε-caprolactone.

Most preferably, the aliphatic polyesters used in the matrices of thepresent invention consist of homopolymers of poly(ε-caprolactone),poly(p-dioxanone), or poly(trimethylene carbonate) or copolymers ormixtures thereof, or copolyesters of p-dioxanone or trimethylenecarbonate and glycolide or lactide or mixtures thereof, and inparticular, copolymers of p-dioxanone/glycolide, p-dioxanone/lactide,trimethylene carbonate/glycolide and trimethylene carbonate/lactide, orcopolyesters of .epsilon.-caprolactone and glycolide or mixturesthereof, or mixtures of homopolymers of ε-caprolactone and lactide.

In a specific embodiment of the present invention, a biocompatible,non-absorbable, flowable polymer whose melting point is from about 45°C. to about 75° C. and which is a rigid solid at body temperatures belowabout 42° C. is placed in a standard Toomeytype disposable syringe witha 35 mm diameter and appropriate capacity of about 50-100 milliliters.The filled syringe is placed in a peel-apart package for steriledelivery and sterilized with cobalt radiation or heat, the former beingpreferred. Alternatively, the polymer can be placed in a squeeze bottleof suitable capacity and having a slit orifice.

In some embodiments, the strut comprises at least 90 wt % calciumphosphate. According to Hitchon et al. J. Neurosurg. (Spine 2) (2001),95:215-220, the entire teachings of which are incorporated herein byreference, the compressive strength of hydroxyapatite is about 65 MPaand the tensile strength of hydroxyapatite is about 10.6 MPa. Thepresent inventors believe that these values should satisfy typical strutload requirements.

In some embodiments, the matrix is made of a cross-linkable compound. Ingeneral, cross-linkable compounds cross-link in-situ and provide highercompressive strengths (typically on the order of 20-120 MPa) thanheat-flowable polymers (typically on the order of 1-20 MPa.

In some embodiments, the cross-linkable compound comprises anunsaturated linear polyester.

In some embodiments, the unsaturated linear polyester comprises afumarate double bond, and more preferably comprises polypropylenefumarate.

In some embodiments, the cross-linkable compound is cross-linked by amonomer, preferably a vinyl monomer, more preferably vinyl pyrrolidone.

In some embodiments, the links produced by the cross-linking agent arebiodegradable. Preferred embodiments thereof include polypropylenefumarat-diacrylate.

In some embodiments, the cross-linking reaction is aided by aninitiator. In preferred embodiments, the initiator is benzoyl peroxide.In other, light is used as the photoinitiator.

In some embodiments, the cross-linking reaction is aided by anaccelerant. In preferred embodiments, the accelerant isN,N-Dimethyl-p-toluidine.

It is believed that the terminal functional groups affect the strengthand degradation resistance of the cross-linked matrix. In someembodiments, the cross-linked compound is terminated by a terminal groupselected from the group consisting of diepoxide, or diacryal functionalgroups. In preferred embodiments, the terminal groups are diepoxidefunctional groups. These terminal functional groups were shown to bemore resistant to degradation than divinyl terminated polypropylenefumarat (Domb 1996).

In some embodiments, a porogen such as NaCl or a foaming agent is addedto the cross-linkable composition. Preferably, the porogen is watersoluble, more preferably it is a water soluble salt or sucrose.

In some embodiments, a calcium phosphate based compound, such ashydroxyapatite or tricalcium phosphate, is added to the cross-linkablecomposition. These compounds are desirable because they can provide anosteoconductive pathway for bone growth, they can neutralize any acidproduced from hydrolysis of the polymer matrix, and providereinforcement. Preferably, the calcium phosphate is nano high aspecthydroxyapatite.

In some embodiments, the strut of the present invention comprises a loadbearing composition comprising a fumarate-based polymer (such aspolypropylene fumarate) cross-linked with a cross-linking agentcontaining a polupropylene fumarate-unit, such as polypropylenefumarate-diacrylate. Exemplary compositions are disclosed in Timmer,Biomaterials (2003) 24:571-577, the entire teachings of which areincorporated herein by reference. These compositions are characterizedby a high initial compressive strength (about 10-30 MPa) that typicallyincreases over the first 12 weeks, high resistance to hydrolyticdegradation (about 20-50 at 52 weeks), and an acceptable modulus for useas a strut (0.5-1.2 GPa).

In preferred embodiments, the polypropylene fumarate: polypropylenefumarate-diacrylate double bond ratio is between about 0.1 and about 3.In more preferred embodiments, the polypropylene fumarate-diacrylatedouble bond ratio is between about 0.25 and about 1.5.

In more preferred embodiments, the load bearing composition comprisingpolypropylene fumarate cross-linked by polypropylene fumarate-diacrylatefurther comprises tricalcium phosphate (TCP), preferably in an amount ofbetween about 0.1 wt % and about 1 wt %. This composition ischaracterized by a high initial compressive strength (about 30 MPa) thattypically increases over the first 12 weeks (to about 45 MPa), a highresistance to hydrolytic degradation (about 45 MPa at 52 weeks), and anacceptable modulus for use as a strut (1.2 GPa at 52 weeks).

In some embodiments, the strut or load bearing composition comprises twocross-linkable polymer compositions. Upon exposure to appropriatecross-linking agents, each of the cross-linkable compositionscross-links with itself, but not with the other cross-linked polymer.The result thereof is a matrix comprising two cross-linked polymers.These are called “interpenetrating networks” (“IPN”).

In other embodiments, the strut or load bearing composition comprises afirst cross-linkable polymer composition and a second non-cross linkablepolymer composition. Upon exposure to an appropriate cross-linkingagent, the first cross-linkable compound cross-links with itself, whilethe second polymer remains unaffected. The result thereof is a matrixcomprising a first cross linked polymer and a second non-cross linkedpolymers. These are called “semi-interpenetrating networks” (“S-IPN”)

In some embodiments, the S-IPNs comprise a first biodegradable polymercapable of producing acidic products upon hydrolytic degradation; asecond biodegradable polymer, which, preferably via crosslinking,provides a biopolymer scaffolding or internal reinforcement; andoptionally a buffering compound that buffers the acidic products withina desired pH range. In a preferred embodiment, the second biodegradablepolymer comprises polypropylene fumarate (PPF) which is cross-linked,desirably by a vinyl monomer such as vinyl pyrrolidone (VP) to form thebiopolymer scaffolding which provides the semi-IPN with the requisitedimensional and geometric stability. A beneficial end use of thismaterial is in the form of internal fixation devices (IFDs) such as bonesupports, plates, and pins, and/or bone cements for bone repair whichare formed from the semi-IPN alloy disclosed herein.

In some embodiments, the S-IPN comprises a bone cement containing abiodegradable polymeric semi-IPN alloy comprising a first biodegradablepolymer (such as PLGA) capable of producing acidic products uponhydrolytic degradation; and a second biodegradable polymer (such aspolypropylene fumarate), which provides a biopolymer scaffolding orinternal reinforcement, wherein the second biodegradable polymer ispolymerized in vivo to provide a hardened, semi-IPN alloy bone cement.Both the bone cement and dimensionally and geometrically stable IFDs ofthe disclosure of the invention may advantageously also contain otheragents such as bone repair proteins (BRPs) and antibiotics, to, e.g.,actively promote bone growth and prevent infection while the bone cementor IFD is in place.

In some embodiments, S-IPNs of the present invention include at leasttwo components. The first component is a linear, hydrophobicbiodegradable polymer, preferably a homopolymer or copolymer whichincludes hydroxy acid and/or anhydride linkages or a linear,non-biodegradable hydrophilic polymer, preferably polyethylene oxide orpolyethylene glycol. The second component is one or more crosslinkablemonomers or macromers. At least one of the monomers or macromersincludes a degradable linkage, preferably an anhydride linkage. Thelinear polymer preferably constituted between 10 and 90% by weight ofthe composition, more preferably between 30 and 70% of the composition.The crosslinked polymer preferably constitutes between about 30 and 70%by weight of the semi-interpenetrating network composition, morepreferably, between 40 and 60 percent of the composition, with thebalance being excipients, therapeutic agents, and other components. Thecompositions form semi-interpenetrating polymer networks when thesecomponents are mixed, and the crosslinkable component is crosslinked.Semi-interpenetrating networks are defined as compositions that includetwo independent components, where one component is a crosslinked polymerand the other component is a non-crosslinked polymer.

These S-IPN compositions can have a viscosity before crosslinkinganywhere between a viscous liquid suitable for injection to a moldable,paste-like putty. The viscosity can be adjusted by adding reactivediluents and/or by adding appropriate solvents. When crosslinked,however, the compositions are solid semi-interpenetrating networks,which are capable of supporting, bone growth and repair.

Linear polymers are defined as homopolymers or block copolymers that arenot crosslinked. Hydrophobic polymers are well known to those of skillin the art. Biodegradable polymers are those that have a half-life underphysiological conditions of between about two hours and one year,preferably less than six months, more preferably, less than threemonths. Examples of suitable biodegradable polymers includepolyanhydrides, polyorthoesters, polyhydroxy acids, polydioxanones,polycarbonates, and polyaminocarbonates. Preferred polymers arepolyhydroxy acids and polyanhydrides. Polyanhydrides are the mostpreferred polymers.

Linear, hydrophilic polymers are well known to those of skill in theart. Non-biodegradable polymers are those that have a half-life longerthan approximately one year under physiological conditions. Examples ofsuitable hydrophilic non-biodegradable polymers include poly(ethyleneglycol), poly(ethylene oxide), partially or fully hydrolyzed poly(vinylalcohol), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers(poloxamers and meroxapols) and poloxamines. Preferred polymers arepoly(ethylene glycol), poloxamines, poloxamers and meroxapols.Poly(ethylene glycol) is the most preferred polymer.

The composition includes one or more monomers or macromers. However, atleast one of the monomers or macromers includes an anhydride linkage.Other monomers or macromers that can be used include biocompatiblemonomers and macromers, which include at least one free-radicalpolymerizable group. For example, polymers including ethylenicallyunsaturated groups, which can be photochemically crosslinked, may beused, as disclosed in WO 93/17669 by the Board of Regents, University ofTexas System, the entire teachings of which are incorporated byreference.

In some embodiments, the cross-linking polymer of the S-IPN comprises afumarate, preferably polypropylene fumarate.

For the purposes of the present invention, the non-cross-linkablepolymer of an S-IPN may also be referred to as a host polymer. In someembodiments, the host polymer for the S-IPN is selected from the groupconsisting of polylactic acid, polyglycolic acid, and their copolymers.

The present inventors have observed that both Hao and Timmer reportsignificantly greater mechanical properties and resistance todegradation when the host polymer is cross linked by a monomer havingthe same repeating unit as the host polymer.

In some embodiments, the cross-linkable compound in the S-IPN iscross-linked by N-vinyl pyrrolidone, polyethylene glycol dimethacrylate(PEG-DMA), ethylene dimethacrylate (EDMA), 2-hydroxyethyl methacrylate(HEMA) or methylmethacrylate (MMA).

In some embodiments, a photopolymerized anhydride is used as the matrixmaterial. These materials are characterized as being strong (compressivestrength 30-40 MPa), and relatively stiff (tensile modulus of about 600MPA to about 1400 MPa).

A. K. Burkoth, Biomaterials (2000) 21:2395-2404, the entire teaching ofwhich are incorporated herein by reference, discloses a number ofphotopolymerizable anhydrides as suitable for orthopaedic use. Therepeating unit of these anhydrides comprises a pair of diacid moleculeslinked by anhydride bonds that are susceptible to hydrolysis. Becausethe diacid molecules are hydrophobic, there is a limited diffusion ofwater into the polymer, and so the polymer is subject only to surfacedegradation (not bulk degradation). This is advantageous because thestrength of the polymer will essentially correspond to the mass of thepolymer.

In some embodiments, the photopolymerized anhydride is selected from thegroup consisting of polymers of methacrylated sebacic acid (MSA),methacrylated 1,6-bis(p-carboxyphenoxy) hexane (MCPH),1,3-bis(p-carboxyphenoxy) propane (CPP), methacrylated cholesterol (MC),methacrylated stearic acid (MstA) and blends and copolymers therefrom.

In some embodiments, the photopolymerization is carried out by adaptinga light source to the distal end of the delivery cannula that enters thedisc space. In other embodiments, a photo-optic cable is used totransmit light energy into the precursor components that have beendeposited in the disc space. In other embodiments, light is transmittedthrough the skin (i.e, transcutaneously) or through the annulusfibrosus. In some embodiments thereof, a photobleaching initiatingsystem is used.

In some embodiments, a linear polyanhydride is first dissolved in amonomer, and then photopolymerized to form a S-IPN of a photopolymerizedanhydride. These are particularly desirable where increased resistanceto hydroysis is desired. Accordingly, in some embodiments, the loadbearing composition of the present invention comprises a S-IPNcomprising a photopolymerized anhydride.

In some embodiments, poly (1,6-bis(p-carboxyphenoxy)hexane (PCPH) isused. This polymer has a degradation of about 496 days, and so isdesirably used as the load bearing composition in a strut of the presentinvention.

Polymerization is preferably initiated using photoinitiators.Photoinitiators that generate an active species on exposure to UV lightare well known to those of skill in the art. Active species can also beformed in a relatively mild manner from photon absorption of certaindyes and chemical compounds.

These groups can be polymerized using photoinitiators that generateactive species upon exposure to UV light, or, preferably, usinglong-wavelength ultraviolet light (LWUV) or visible light. LWUV andvisible light are preferred because they cause less damage to tissue andother biological materials than UV light. Useful photoinitiators arethose, which can be used to initiate polymerization of the macromerswithout cytotoxicity and within a short time frame, minutes at most andmost preferably seconds.

Exposure of dyes and co-catalysts such as amines to visible or LWUVlight can generate active species. Light absorption by the dye causesthe dye to assume a triplet state, and the triplet state subsequentlyreacts with the amine to form an active species, which initiatespolymerization. Polymerization can be initiated by irradiation withlight at a wavelength of between about 200-700 nm, most preferably inthe long wavelength ultraviolet range or visible range, 320 nm orhigher, and most preferably between about 365 and 514 nm.

Numerous dyes can be used for photopolymerization. Suitable dyes arewell known to those of skill in the art. Preferred dyes includeerythrosin, phloxime, rose bengal, thonine, camphorquinone, ethyl eosin,eosin, methylene blue, riboflavin, 2,2-dimethyl-2-phenylacetophenone,2-methoxy-2-phenylacetophenone, 2,2-dimethoxy-2-phenyl acetophenone,other acetophenone derivatives, and camphorquinone. Suitable cocatalystsinclude amines such as N-methyl diethanolamine, N,N-dimethylbenzylamine, triethanol amine, triethylamine, dibenzyl amine,N-benzylethanolamine, N-isopropyl benzylamine. Triethanolamine is apreferred cocatalyst.

Photopolymerization of these polymer solutions is based on the discoverythat combinations of polymers and photoinitiators (in a concentrationnot toxic to the cells, less than 0.1% by weight, more preferablybetween 0.05 and 0.01% by weight percent initiator) will crosslink uponexposure to light equivalent to between one and three mWatts/cm.sup.2applied to the skin of nude mice.

In some embodiments, the matrix comprises a co-polymer having shapememory qualities. In preferred embodiments, the shape memory polymercomprises a first crosslinkable monomer and a second monomer havingshape memory qualities. Preferably, the linear polyester has a molecularweight of at least 10,000. Preferably, the first monomer is a linearpolyester. Preferably, the second shape memory monomer is n-butylacrylate. Preferably, cross-linking is induced without an initiator.

Preferably, the shape memory polymer comprises between about 70 wt % andabout 90 wt % of the first crosslinkable monomer and between 10 and 30wt % of the a second monomer having shape memory qualities.

Preferably, the shape memory polymer matrix has a compressive strengthof at least 15 MPa. This would make it a suitable candidate as a loadbearing composition in a strut of the present invention.

Representative shape memory matrices are disclosed in Lendlein, PNAS,98(3), Jan. 30, 2001, pp. 842-7, the entire teachings of which areincorporated herein by reference, which discloses polycaprolactone asthe first linear polyester. In other embodiments, polylactic acid is thefirst linear polyester. It is believed that polylactic acid wouldprovide a strong, stiffer matrix, more suitable for use as a loadbearing composition in the strut of the present invention.

In one embodiment, the S-IPN comprises:

-   -   a) a first part comprising a first bioerodible polymer capable        of producing acidic products upon hydrolytic degradation, and    -   b) a second part comprising a second bioerodible scaffolding        polymer, which upon crosslinking provides a biopolymeric        scaffolding or internal reinforcement for the S-IPN, and a        crosslinking agent for the second bioerodible scaffolding        polymer.

In more preferred embodiments, the S-IPN comprises:

-   -   a) a first part comprising a first bioerodible polymer capable        of producing acidic products upon hydrolytic degradation, a        crosslinking initiator, and preferably, a therapeutically        effective amount of a biologically active or therapeutic agent        and a combination of citric acid and sodium bicarbonate; and    -   b) a second part comprising a second bioerodible scaffolding        polymer, which upon crosslinking provides a biopolymeric        scaffolding or internal reinforcement for the S-IPN, and a        crosslinking agent for said second bioerodible scaffolding        polymer.

In general, many of the resorbable materials are believed to have onlymoderate strength and stiffness. Therefore, it may be desirable toincrease the strength and stiffness of the strut's matrix material byadding reinforcements to the matrix. Although the fibers can be made ofnon-resorbable materials (such as chopped carbon fibers), preferably thereinforcements are made of materials that are also resorbable.

In some embodiments, the fiber comprises carbon fiber. Preferably,carbon fiber comprises between about 1 vol % and about 60 vol % (morepreferably, between about 10 vol % and about 50 vol %) of the loadbearing composition. In some embodiments, the polymer and carbon fibersare homogeneously mixed. In others, the material is a laminate. In someembodiments, the carbon fiber is present as chopped state. Preferably,the chopped carbon fibers have a median length of between 1 mm and 12mm, more preferably between about 4.5 mm and about 7.5 mm. In someembodiments, the carbon fiber is present as continuous strands.

Biodegradable polymers are known, commercially available, or can besynthesized into fibers using known and published methods. Examples ofpolymers useful in the present invention include poly(L-lactic acid),poly(D,L-lactic acid), poly(D L-lactic-co-glycolic acid), poly(glycolicacid), poly(epsilon-caprolactone), polyorthoesters, and polyanhydrides.These polymers may be obtained in or prepared to the molecular weightsand molecular weight distribution needed for service as either thematrix polymer or the pore-forming polymer by processes known in theart. Preferred polymers are poly(alpha-hydroxy esters). Suitable solventsystems are known in the art and are published in standard textbooks andpublications. See, for example, Lange's Handbook of Chemistry,Thirteenth Edition, John A. Dean, (Ed.), McGraw-Hill Book Co., New York,1985, the entire teachings of which are incorporated herein byreference. These polymers may be formed into fibers and webs by standardprocessing techniques including melt extrusion and spin casting, and arecommercially available in woven or non-woven form.

In some embodiments, p-dioxanone fibers are used as the reinforcingphase of the strut. These fibers are advantageous because the highmelting point of p-dioxanone resists any thermal degradation of thefibers during injection into the disc space.

In some preferred embodiments, the strut compositions comprise aliphaticpolyesters reinforced with p-dioxanone fibers. In more preferredembodiments, those compositions disclosed in U.S. Pat. No. 6,147,135 byYuan (hereinafter “Yuan”), the specification of which is incorporatedherein by reference in its entirety, are selected.

In some embodiments, both the osetobiologic composition and the strutare bioresorbable. The selection of a bioresorbable strut isadvantageous because it reduces the amount of foreign materials left inthe body.

In some embodiments load-bearing component is used alone.

If desired, the strut material can also include bone growth materials,such as growth factors and stem cells that promote bone growth uponeventual resorption of the resorbable strut. However, since the stemcells must typically be housed in an aqueous phase (such as a hydrogel),the inclusion of stem cells likely requires the introduction of aporosity into the strut that may significantly degrade the strength ofthe strut. Since the primary purpose of the strut is to support the discspace while the osteogenic composition promotes fusion, adding stemcells to the strut composition may not be fully desirable in allcircumstances. Therefore, in preferred embodiments, only growth factorsare added to the strut composition.

In one embodiment, the growth factors are first provided in an aqueoussolution and particles of the resorbable strut material are added to thesolution. The growth factors cling to the outer surface of theparticles. Next, the growth factor-laden particles are separated fromthe growth factor solution. Next, the growth factor-laden particles areadded to the viscous resorbable material.

In some embodiments, the device of the present invention has at leastone of the following characteristics:

Desired Typical Specification Range of Values Range of Values UltimateLoad >5 kN 5-25 kN in Axial Compression Stiffness >5 kN/mm 5-25 kN/mm inAxial Compression Ultimate Load >2 kN 2-6 kN in Compression ShearStiffness >3 kN/mm 3-9 kN/mm in Compression Shear Ultimate Load >5 N-m5-20 N-m in Static Torsion Stiffness >>1 kN/mm 1-4 kN/mm in CompressionShear

In some embodiments, the material comprising the strut of the presentinvention has at least one of the following intrinsic properties:

Intrinsic Property Preferred Value More Preferred Value CompressionStrength >11 MPa >25 MPa Fracture Strength >20 MPa >40 MPa CompressionModulus 0.1-10 GPa 0.5-2 GPa

In some embodiments, the strut device of the present invention has atleast one of the following mechanical performance characteristics:

Mechanical Property Preferred Value More Preferred Value StaticCompressive Load >2 kN >4 kN Cyclic Comp. Load (10⁶ cycles) >1 kN >2 kN

One example of this embodiment is shown in FIGS. 2 (f) and (g). Thearcuate shape has a thickness (t) of 3 mm, inner radius (r_(i)) of 22mm, an outer radius (r_(o)) of 25 mm and an average height if 15 mm.When this device is produced from a photopolymerized polyanhydride withan intrinsic compressive strength of 30 MPa and compressive modulus of 1GPa, the static compressive load required to fail the device is 6.6 INand the compressive stiffness is 15 kN/mm.

In some embodiments, the novel struts of the present invention can beused with conventional osteobiologic materials, such as platelet-richplasma (PRP), allograft particles (such as demineralized bone matrix(DBM) and cancellous chips) and autograft.

In preferred embodiments, the osteobiologic component of the presentinvention acts in a manner similar to the cancellous core of a vertebralbody. Desirable features for the osteobiologic composition of the strutare as follows:

-   -   a) strength similar to that of cancellous bone;    -   b) stiffness similar to that of cancellous bone (or, in        relatively large footprint embodiments, cortico-cancellous        bone);    -   c) mild degradation resistance (e.g., degrades in manner that        allows bone growth therethrough; and    -   d) resorbable.

As noted above, in preferred embodiments, the in-situ formedosteobiologic composition comprises:

-   -   a) a matrix material (preferably, a polymer flowable at between        40° C. and 80° C.; a linear anhydride, or a fumarate,    -   b) osteogenic component (preferably, mesenchymal stem cells        present in a concentrated amount), and    -   c) an osteoinductive factors (preferably, a bone morphogenetic        protein).

Examples of matrices that could be used in the osteobiologic componentinclude ceramics comprising calcium phosphate such as, for example,hydroxyapatite or tri-calcium phosphate, polylactic acid, polyglycolicacid, polygalactic acid, polycaprolactone, polyethylene oxide,polypropylene oxide, polysulfone, polyethylene, and polypropylene,hyaluronic acid, which may be purified with or without crosslinking,bioglass, gelatin and collagen.

Preferably, the matrix is a resorbable composition that resorbs within a2-4 month time period after in-situ formation and comprises:

-   -   a) a polymer phase that flows or softens at a temperature of        between 40° C. and 80° C. (more preferably, comprising an        aliphatic polyester such as polycaprolactone) and is preferably        present in an amount of between 50 vol % and 70 vol % of the        osteobiologic composition, and    -   b) an osteoconductive calcium phosphate phase (more preferably        hydroxyapatite) preferably present in an amount of between 10        vol % and 30 vol % of the osteobiologic composition.

Optionally, a reinforcing phase (preferably, resorbable polymericchopped fiber) is also preferably present in an amount of between about10 vol % and, about 30 vol % of the osteobiologic composition.

Preferably, the osteogenic component comprises an aqueous phase(preferably a hydrogel phase) having viable osteoprogenitor cells(preferably mesenchymal stem cells) present therein in a concentratedamount. Preferably, the aqueous phase is present as an interconnectedphase throughout the osetobiologic composition, and is present in anamount of between about 25 vol % and about 35 vol % of the osteobiologiccomposition and has an average diameter of between 100 and 250 μm.

Preferably, the osteoinductive factor is selected from the groupconsisting of a bone morphogenetic protein and a transforming growthfactor. More preferably, the osteoinductive factor is a bonemorphogenetic protein. The bone morphogenetic protein may be present inany phase of the osteobiologic composition. When immediate delivery ofthe bone morphogenetic protein is desirable, the bone morphogeneticprotein is present in the hydrogel phase. When intermediate delivery ofthe bone morphogenetic protein is desirable, the bone morphogeneticprotein is present in the polymer phase. When long term delivery of thebone morphogenetic protein is desirable, the bone morphogenetic proteinis present in the ceramic phase. It is preferable to have at least twicethe autologous level of bone morphogenetic protein, and more preferably,at least 10 times the autologous level of bone morphogenetic protein.

In one preferred embodiment, the matrix comprises a material having amelting point between about 42° C. and about 95° C., (preferably betweenabout 42° C. and about 90° C.) which allows it to be flowed into thedisc space without causing tissue necrosis, and then in-situ solidifiedto provide the needed structural support. The scaffold material furthercomprises a porogen that allows it to be made into a porous scaffold byconventional leaching techniques. Lastly, growth factors andosteoprogenitor cells such as mesenchymnal stem cells can be flowedthrough the open porosity of the scaffold to induce bone growththroughout the scaffold.

In another preferred embodiment, mesenchymnal stem cells are isolatedfrom a bone marrow aspirate taken from the patient and incorporated intobioabsorbable particles capable of maintaining cell viability, such ashydrogels. Preferably the hydrogels will absorb quickly such that thecells will be released to form bone. The particulate are then mixed witha scaffold material in a first liquid form that will solidify uponimplantation. Preferably, the scaffold material resorbs slowly such thatbone can be formed throughout the porosity before the scaffold degradesaway. Preferred scaffold materials are polymers that can be dissolved ina cell-friendly solvent such as dimethyl sulfoxide (DMSO), which willleach out once implanted, causing the polymer to precipitate out ofsolution and create a solid scaffold. Preferably a growth/nutritivefactor cocktail for inducing the osteoprogenitor cells to form bone andcontinue to support the bone formation process is incorporated into thecell-seeded hydrogel as well as the scaffold material. Following discspace preparation the system is injected to the disc space and no othersurgical steps are required.

In some aspects of the present invention, there is provided an in-situformed (and preferably injectable) intervertebral fusion devicecomprising:

-   -   a) a porous scaffold having a porosity suitable for new bone        formation,    -   b) viable osteoprogenitor cells, and    -   c) osteoinductive factors required to signal the osteoprogenitor        cells to form new bone.

Porous scaffolds that can form upon injection through a minimallyinvasive surgical procedure can be made of a material selected from thegroup consisting of crosslinked natural and synthetic polymers, lowmelting point polymers, polymers dissolved in biocompatible solvents,and setting ceramics. Porous scaffolds suitable for use in the presentinvention are disclosed in U.S. Pat. Nos. 6,280,474 and 6,264,695(swellable polymers), U.S. Pat. No. 5,888,220(polycaprolactone/polyurethane), U.S. Pat. No. 6,224,894 (absorbablepolyoxaester hydrogels) and U.S. Pat. No. 6,071,982, the entireteachings of the forgoing U.S. patents are incorporated herein byreference.

In many embodiments, the resorbable polymers, calcium phosphates andreinforcing phases disclosed above in the description of the strut maybe used to form the preferred matrix. In general, the matrix issubstantially weaker (owing to the presence of either open porosity oran interconnected hydrogel phase) than the strut, and hydrolyzesquicker.

In one aspect of the present invention, the matrix has a firstabsorbable phase of about 1 weight percent to about 99 weight percent ofany of the aliphatic homopolyesters of ε-caprolactone, p-dioxanone, ortrimethylene carbonate or copolymers or mixtures thereof, with theremaining resorbable phase comprising a bone osteoconductive orosteoinductive calcium containing, non-fibrous, powdered compound,preferably a calcium phosphate such as hydroxyapatite, tri- ortetra-calcium phosphate, or a bioactive glass, or mixtures thereof.

In a further aspect of the present invention, the matrix has a firstabsorbable phase of about 1 weight percent to about 99 weight percent ofaliphatic copolyesters of p-dioxanone or trimethylene carbonate, andglycolide or lactide or mixtures thereof, and in particular, copolymersof p-dioxanone/glycolide, p-dioxanone/lactide, trimethylenecarbonate/glycolide and trimethylene carbonate/lactide, with a remainingresorbable phase comprising a bone osteoconductive or osteoinductivecalcium containing, non-fibrous, powdered compound, preferably a calciumphosphate such as hydroxyapatite, tri- or tetra-calcium phosphate, or abioactive glass, or mixtures thereof.

In a further aspect of the present invention, the matrix has a firstabsorbable phase of about 1 weight percent to about 99 weight percent ofaliphatic copolyesters of ε-caprolactone and glycolide or mixturesthereof, or mixtures of homopolymers of ε-caprolactone and lactide, witha remaining resorbable phase comprising a bone osteoconductive orosteoinductive calcium containing, non-fibrous, powdered compound,preferably a calcium phosphate such as hydroxyapatite, tri- ortetra-calcium phosphate, or a bioactive glass, or mixtures thereof.

The above-noted matrices will contain sufficient amounts of theabsorbable polymer phase and sufficient amounts of the resorbable secondbone regenerating phase to effectively function as bone cements or bonesubstitutes. Typically, the composites will contain about 1 to about 99weight percent of polymer phase, and more preferably about 5 to about 95weight percent. The composites will typically contain about 1 to about99 weight percent of the bone regenerating phase, and more preferablyabout 5 to about 95 weight percent.

It will be appreciated by those skilled in the art that the relativeamounts of the first absorbable, polymeric phase to the secondresorbable phase in the above-noted matrices will depend upon variousparameters including, inter alia, the levels of strength, stiffness, andother physical and thermal properties, absorption and resorption rates,setting and hardening rates, deliverability, etc., which are required.The desired properties of the composites of the present invention andtheir level of requirement will depend upon the body structure areawhere the bone cement or substitute is needed. Accordingly, thecomposites of the present invention will typically contain about 1weight percent to about 99 weight percent, and more preferably about 5weight percent to about 95 weight percent of aliphatic polyester homo-or co-polymers, or blends thereof.

A further aspect of the present invention is a process by which thematrix component of the osteobiologic composition is prepared. Thematrix can be prepared by a one-step or a two-step process in which abone regenerating material is mixed in the reaction vessel with ajust-formed polymer (one-step process), or mixed with a preformedpolymer in a separate vessel (two-step process).

The composites of the present invention can be manufactured in thefollowing two-step process. The preformed polymers and bone regeneratingmaterials are individually charged into a conventional mixing vesselhaving a conventional mixing device mounted therein such as an impeller.Then, the polymers and bone substitutes are mixed at a temperature ofabout 150° C. to about 220° C., more preferably about 160° C. to about200° C., for about 5 to about 90 minutes, more preferably for about 10to about 45 minutes, until a uniformly dispersed composite is obtained.Then, the composite is further processed by removing it from the mixingdevice, cooling to room temperature, grinding, and drying underpressures below atmospheric at elevated temperatures for a period oftime.

In addition to the above manufacturing method, the composites can beprepared by a one-step process by charging the bone regeneratingmaterial to a reaction vessel which contains the just-formed polymers.Then, the polymers and bone substitutes are mixed at a temperature ofabout 150° C. to about 220° C., more preferably about 160° C. to about200° C., for about 5 to about 90 minutes, more preferably for about 10to about 45 minutes, until a uniformly dispersed composite is obtained.Then, the composite is further processed by removing it from the mixingvessel, cooling to room temperature, grinding, and drying underpressures below atmospheric at elevated temperatures for a period oftime.

In other embodiments, the matrix of the present invention includes abone implant material, which can be readily molded at a selectedtemperature at or below about 60° C. The material is formed as acohesive mixture of hard filler particles and a binder composed of abiocompatible, biodegradable thermoplastic polymer having fluid-flowproperties at the selected temperature at or below about 60° C.

Any hard biocompatible filler particles, including autogenous bonechips, can be used in this invention. However hydroxyapatite is apreferred filler for its permanance and biological profile. Tricalciumphosphate and glass granules may also be used alone or in combinationwith hydroxyapatite, particularly if some degree of resorption isdesired in the filler.

The binder preferably ranges in fluid-flow properties (flowability)between a highly viscous fluid and a putty-like semi-solid, at theselected temperature. With too low a binder viscosity, the implantmaterial suffers the same problems seen in loose-particle implants: poorshape retention, once molded, and poor cohesiveness, leading toexfoliation of particles before or during the tissue ingrowth period. Ina preferred embodiment, the polymer includes polylactic acid having amolecular weight between about 400 and about 5,000 daltons.

The binder preferably constitutes no more than about one-third of thetotal solid volume of the material, leaving void space in the material,which can accommodate tissue ingrowth. The minimum amount of binder isthat necessary to give easy formability and provide sufficient particlecohesion and shape retention during the period of tissue ingrowth.

By similar methods, polylactic acid having progressively greatermolecular weights between about 2,000 and about 5,000 daltons wereprepared and tested for binder characteristics when formulated withhydroxyapatite particles. Above about 2,000 daltons, the implantmaterial was quite hard and difficult to mold by hand at 40° C., and at5,000 daltons, temperatures up to about 60° C. were required to achievemoldability.

To form the implant material of the invention, the binder from above ismixed with hydroxyapatite particles, and the components are thoroughlyblended. Preferably the material contains some void space, to allowtissue ingrowth independent of polymer breakdown. Since the void spaceof a mass of spherical particles is about one-third that of the particlemass, the implant material preferably contains less than about one-thirdby volume of binder. To optimize the void space, the minimum amount ofbinder needed to produce good particle cohesiveness, typically betweenabout 5% and 20% of the total solid volume of the material, is added. Inone embodiment, implant material containing 80% hydroxyapatite particles(average particle size of about 650 microns), and 20% of polylactic acidpolymer having average polymer molecular weights of about 1,100 daltonswas prepared. The material was easily moldable by hand at 50° C., andshowed good cohesiveness and shape retention at 37° C.

In practicing the invention, there is provided a moldable hydroxyapatitebone-implant material. As described above, implant material having arange of molding temperatures and biodegradability can be provided, byadjusting the composition and amount of binder in the material. Materialhaving a relatively high molding temperature, e.g., between about 40° C.to about 60° C., is generally preferred where the implant needs to be ina relatively rigid condition during the process of tissue ingrowth, forexample, to prevent significant shape deformation. Here the material isapplied and shaped to the bone site in a heated state; after cooling, itassumes the desired rigid condition.

The material can be formulated with thermoplastic polymer binders ofvarious composition and molecular weights, to achieve a selected moldingtemperature, rigidity in the bone site, and rate of binder breakdown. Byvarying the relative proportions of binder and particles, selectedchanges in the void space and cohesiveness of the material are possible.

Matrix scaffold polymers can also be produced by first dissolving thepolymer in a biocompatible, water-soluble solvent, injecting thematerial into the disc space, and then allowing the solvent to leach outof the polymer into the body, thereby causing the polymer to solidify invivo. Suitable polymers compatible with such solvents include, but arenot limited to, poly(lactic acid), poly(glycolic acid) and copolymerstherefrom. Suitable biocompatible, water-soluble solvents includedimethylsulfoxide (DMSO). Preferably, the volume ratio of polymer tosolvent is at least 1:5, more preferably at least 1:2. By maximizing theamount of polymer in the polymer/solvent injection, the amount ofstructural material solidified in the body is maximized while minimizingthe amount of solvent to be excreted by the body.

Injectable ceramics can also serve as components in the matrix of theosteobiologic component. Preferred injectable, resorbable ceramics areamorphous calcium phosphates or hydroxyapatites. (See U.S. Pat. Nos.6,214,368 and 6,331,312, the entire teachings of which are incorporatedherein by reference.)

In some embodiments of the present invention, porosity is produced inthe matrix to produce a porous scaffold material. Once in-situ porosityis produced in the osetobiologic composition, the surgeon can theninject an osteogenic component (such as mesenchymnal stem cells) or anosteoinductive component (such as bone morphogenetic protein) into theporosity, thereby enhancing the ostobiologic nature of the composition.

Providing porosity in-situ allows the matrix of the osteobiologiccomposition to comprise materials such as polymers that flow attemperatures only well above body temperature. For example, manypolymers such as polycaprolactone flow at about 60° C., a temperaturethat may well destroy the viability of mesenchymnal stem cells containedwithin the flowable polymer.

Therefore, in some embodiments of the present invention, polymericmaterials that become flowable above 45° C. are first made flowable byraising their temperature to at least 45° C., the flowable polymer isthen injected into the disc space, the in-situ formed material is thenmade porous, and porous material is then injected with mesenchymnal stemcells.

In some embodiments of the present invention, in-situ porosity isaccomplished by first delivering the matrix material into the disc spaceas beads, then tightly packing the beads within the disc space, and thenbonding the beads, preferably by heat bonding, into a stable structure.

In some embodiments of the present invention, porosity is produced inthe matrix to including a foaming agent in the matrix material.

According to another embodiment, porous injectable graft materials areoptionally made by adding a degradable gas-producing compound. As gasbubbles are produced from the gas-producing compound, pores are formedin the bone-like materials. The size of the pores are preferablycontrolled by adjusting the amount of gas-producing compound and theviscosity of the mineral matrix in the fluid used to mix the materials.In a specific embodiment, sodium bicarbonate and/or calcium bicarbonateis added to the flowable matrix material and a precise amount of acid(e.g. citric acid, formic, acetic, phosphoric acids, hydrochloric acid)is added to the mixing fluid. The acidity of the mixing fluid causescarbon dioxide to be released from the sodium bicarbonate, wherein thecarbon dioxide ultimately forms pores in the matrix material. In analternative embodiment, hydrogen peroxide is combined with peroxidase inthe graft material. The peroxidase releases oxygen from the hydrogenperoxide, which has the added advantage of sterilizing the wound site.

In some embodiments of the present invention, in-situ porosity can beproduced in the matrix material including a porogen with the matrixmaterial, and then in-situ leaching out of the porogen. Preferably, aporogen is a water-soluble materials. Biodegradable materials can befabricated into three dimensional anatomical shapes having load bearingproperties similar to or exceeding that of natural bone. A matrixcomponent of the osteobiologic component has the capability of beingrendered porous and can serve to foster bony fusion. In theseembodiments, the osteobiologic composition can be implanted withoutfirst being rendered to its porous state. Porosity can be achieved afterimplantation by a faster rate of biodegradation of a pore-formingcomponent of the osteobiologic component relative to a slower rate ofdegradation of the matrix component of the osteobiologic component. Theporous osteobiologic component has sufficient compressive strength andmodulus to serve as a bone replacement prosthesis during that periodwherein the body regenerates new natural bone within and to the shape ofthe osteobiologic component. Ultimately, the osteobiologic component isreplaced by natural bone as the osteobiologic component biodegrades andby such process is displaced or eliminated from the body by naturalprocesses.

In such embodiments, the osteobiologic composition comprises at leasttwo components, a continuous matrix component and an includedpore-forming component. The matrix component comprises a biodegradablematerial having a rate of degradation, which at least matches the rateat which the body regenerates natural bone tissue. The pore-formingcomponent is a material, which differs from the matrix material suchthat it may be differentiated from the matrix component and ultimatelybe removed therefrom by differential dissolution or biodegradation toprovide porosity to the prosthetic template either prior to or afterimplantation.

Unless wholly removed from the matrix polymer of the implant beforeimplantation, the molecular weight, molecular weight distribution anddegree of crystallinity of the pore-forming polymer is also ofsignificant concern. Generally, the pore-forming polymer shouldbiodegrade and/or bioresorb at a rate that is at least four timesgreater than that of the matrix polymer. Further, the pore-formingpolymer should have a polydispersity index of at least 3 to provide fora controlled degradation over a period of time that avoids intolerablelocalized pH concentrations due to its degradation by-products.

The osteobiologic compositions of these embodiments can contain arelatively high ultimate porosity capacity. That is, the osteobiologiccomposition is fabricated in a manner, which results in an osteobiologiccomponent capable of being rendered highly porous prior to implantation.For example, the matrix may be formed around included particles orfibers which particles or fibers are subsequently removed from thematrix by solvent dissolution or other methods of degradation, leaving ahighly porous matrix scaffold structure. Alternatively, the particles orfibers embedded within the formed matrix may be retained in theosteobiologic composition for dissolution or degradation in situ afterimplantation. In addition, portions of the pore-creating material may beremoved prior to implantation of the osteobiologic composition providinga range of actual to ultimate porosities of the implantableosteobiologic components.

The ultimate porosity capacity may be defined as the percent porosity ofthe matrix after at least 90% of the pore forming material has beenremoved from the template, either in vitro or in vivo. In the presentinvention, it is preferred that the ultimate porosity capacity of thebiodegradable/bioresorbable osteobiologic component be in the range ofbetween about 20% and about 50% volume of the osteobiologic component.

The biodegradable osteobiologic composition of the present invention,which has the porogen features described above, including highmechanical strength necessary for replacement of load bearing bones,high ultimate porosity capacity to permit bony fission therethrough, anda rate of degradation approximately matching the rate of new tissuegrowth may, for example, be formed by the methods described below. Inits simplest embodiment, these osteobiologic compositions of the presentinvention are formed by distributing within a polymeric matrix apore-creating substance (or “porogen”). Regardless of the specificmethods used to form the osteobiologic composition, the product willinclude a three-dimensional, anatomically-shaped osteobiologiccomposition having a high ultimate porosity capacity due to the presenceof a pore creating substance dispersed within the matrix.

The pore creating substance may be formed for example of salts,polysaccharides, protein, polymers other than the matrix polymers, orother non-toxic materials such as gelatin which are, for example,soluble in a solvent which does not dissolve the matrix polymer; madefluid at a higher glass transition temperature (Tg) or meltingtemperature (Tm) than the matrix polymer; or otherwise differentiatedfrom the matrix polymer so as to retain an independent structure fromthe polymeric matrix. When subsequently removed, the desired pores areformed within the matrix.

The temperature required to fluidize polymers is that which permitsnon-hindered flow of polymer chains. For amorphous polymers, this “flowtemperature” is the glass transition temperature (Tg). However, forsemi-crystalline polymers this “flow temperature” is the meltingtemperature (Tm). As used herein, flow temperature is meant to be thattemperature which permits non-hindered flow of polymer chains andincludes, as appropriate, Tg for amorphous polymers and Tm for at leastsemi-crystalline polymers.

The pore creating substance may be in the form of particles such assalt, which after forming a matrix in which the particles have beenincluded, the particles are leached out or otherwise removed from thematrix leaving a polymeric matrix with high porosity. The pore creatingsubstance may be in the form of fibers such as polymeric fibers or websdispersed within a formed polymeric matrix. The dispersed fibers and thesurrounding matrix possess differential rates of degradation, with thefibers being degraded at a faster rate than the matrix, thereby beingremoved from the osteobiologic composition and creating a highly porouspolymeric, osteobiologic composition.

The porogen-containing osteobiologic composition may be formed bydispersing the pore-creating substance in a body of powdered polymer.Preferably, the pore-creating substance is a first polymer in fiber orweb form dispersed in a body of powdered second polymer. The secondpolymer has a lower flow temperature (Tf) such that when the dispersionis heated above the flow temperature of the powder, the powder is fluid,but the dispersed fibers are not. The fluid polymer is next solidified,e.g., by permitting the dispersion to return to ambient temperature,resulting in a polymeric matrix having entrapped therein thepore-forming substance.

In a preferred embodiment, a first polymer is used to form the matrixand a second polymer is used to form the pore-creating substancedispersed within the first polymer. Both first and second polymers arebiodegradable but the second degrades at a faster rate than the firstpolymer, e.g., approximately two to eight times faster, and preferablyabout four times faster creating the desired porous body for ingrowthand proliferation of cells. For example, poly(glycolic acid) (PGA) fibermeshes may be dispersed within poly(L-lactic acid) (PLLA). Upon curingof the PLLA matrix, the PGA fiber mesh is embedded within the PLLAmatrix. The PGA fibers biodegrade at a more rapid rate than PLLA, thuscreating a template having a high ultimate porosity capacity.

The pore creating substance may be formed of a low molecular weightpolymer while the matrix is formed of a high molecular weight polymer.Because the low molecular weight polymers degrade at a faster rate thanthe high molecular weight polymers an implant having a desired rate ofdegradation of each of the pore creating substance and the matrix can beformed.

In vivo degradation of the pore-creating substance at a faster rate thanthe template matrix, such as PGA fibers which degrade within months ofimplantation in a PLLA matrix which may take more than one year todegrade, permits gradual replacement of the pore-creating substance withgrowing bone cells. The resorbing pore-creating substance is graduallyreplaced with newly formed bone tissue, maintaining a mechanicallystrong bone prosthesis. The more slowly degrading polymeric matrix isthen resorbed and replaced with bone tissue proliferating from thenetwork of growing tissue already present throughout the prosthetictemplate.

In some embodiments, the matrix has a sufficient number of pores orpassageways so that the total accessible surface area of the substrateis at least five times greater than a solid object having the sameexternal dimensions. Thus, the preferred total surface area can beachieved by using a substrate, which comprises a mass of powder, a massof granules, a mass of fibers, or a highly porous block of substratematerial. Preferably, the average pore size in the matrix is greaterthat 20 μm, more preferably greater than 50 μm, more preferably greaterthan 100 μm. In some embodiments, the pore size is between about 100 μmand 250 μm.

The osteobiologic compositions of the present invention have a highultimate porosity capacity, resulting in a highly porous matrixcontaining a uniformly distributed and interconnected pore structure.Pore volume of the porous osetobiologic composition is approximately 20%to 90%, and the average pore diameter is approximately 50 to 250 μm. Thepore volume and diameter also directly relate to the rate of tissueingrowth and matrix degradation. The porous matrix of the presentinvention accommodates large number of cells adhering to the matrix,permits cells to be easily distributed throughout the template, andallows an organized network of tissue constituents to be formed. Thematrix preferably promotes cell adhesion and permits the attached cellsto retain differentiated cell function. In some embodiments, theleachate produces an open porosity having an average pore size ofbetween 20 μm and 500 μm, preferably 50-250 μm. This range is preferredfor bone growth.

In some embodiments, the matrices of the osteobiologic component arefabricated of polymers and by methods which result in implants which arecapable of being rendered porous for tissue ingrowth while retainingsufficient mechanical strength to be suitable for supporting a discspace. For example, in their preporous state the osteobiologiccompositions of the present invention possess a compressive strength ofapproximately 5 MPa to 50 MPa and a compressive modulus of approximately50 MPa to 500 MPa as tested by an Instron Materials Testing Machineaccording to American Society for Testing and Materials (ASTM) StandardF451-86. The values of 5 MPa compressive strength and 50 MPa compressivemodulus correspond to the mid-range values for human trabecular bone.

The biodegradable, bioresorbable matrices of the present inventionpreferably are formed of polymeric materials, the matrix polymer havinga rate of degradation which is matched to the rate of tissue in-growth.The matrix polymeric substance preferably ranges in weight averagemolecular weight from approximately 50,000 to 200,000. Crystallinity ofthe matrix polymer of implant is approximately 0 to 25%. The molecularweight and molecular weight distribution of the matrix polymer isrelated to the rate at which the matrix biodegrades. In a matrix ofbroad molecular weight distribution, e.g., having a polydispersity index(Mw/Mn) greater than 2 fractions of the material exist in short to longpolymeric chains. This diversity allows a continuation of degradationover time without sharp changes, e.g., in pH due to degradationproducts, as may occur with a material having a narrow molecular weightdistribution. In the present invention, the polydispersity index of thematrix is preferably in the range of 3-6.

In some embodiments possessing in-situ created porosity, mesenchymnalstem cells (“MSCs”) are then delivered into the porous matrix.

In some embodiments, the mesenchymnal stem cells are delivered into theporosity of the scaffold by simply directing an aqueous solutioncontaining mesenchymnal stem cells into the scaffold. In someembodiments, an additional cannula can be placed near the porous matrixto serve as an exit cannula for the fluid.

In some embodiments, a hydrophilic matrix material such as polylacticacid may be used. In these instances, it has been found thatmesenchymnal stem cells do not tenaciously adhere to the surface of thepolylactic acid. Accordingly, in some embodiments, a lining material,such as hydroxyapatite (HA), may be used to line the inner surface ofthe scaffold with a material to which mesenchymnal stem cells moretenaciously adhere. In some embodiments, the linings disclosed in U.S.Pat. No. 5,133,755 by Brekke, the entire teachings of which areincorporated herein by reference (hereinafter “Brekke”), are selected.

In some embodiments, other cell adhesion molecules may be bound to theinner surface of the matrix in order to enhance the adhesion of themesenchymnal stem cells to the scaffold. The term “cell adhesionmolecules” refers collectively to laminins, fibronectin, vitronectin,vascular cell adhesion molecules (V-CAM), intercellular adhesionmolecules (I-CAM), tenascin, thrombospondin, osteonectin, osteopontin,bone sialoprotein, and collagens.

Preferably, the mesenchymnal stem cells are delivered into the in-situporosity under pressure, such as by injection. In these cases, it ishelpful to surround the porous osteobiologic composition with acontaining envelope in order to contain the osteogenic component withinthe in-situ porosity and prevents its leakage outside the osteobiologiccomposition.

In some embodiments, the envelope is the strut component having a 360degree span. In other embodiments, the envelope can be an inflatabledevice component of the osteobiologic composition.

Although it may be useful to create in-situ porosity, it may sometimesbe problematic to evenly distribute the mesenchymnal stem cellsthroughout the in-situ created porosity under normal injectionpressures. In some embodiments of the present invention, themesenchymnal stem cells are delivered into the in-situ porosity under ahigher pressure that is sufficient to fill 90% of the porosity.Preferably, the pressure is high enough to completely fill the porosity.

Therefore, in accordance with the present invention, there is provided amethod delivering an osteogenic component, comprising the steps of:

-   -   a) injecting an osteobiologic composition into a disc space,    -   b) creating in-situ porosity in the osteobiologic component, and    -   c) delivering an osteogenic component into the in-situ porosity        under a pressure of at least sufficient to fill at least 90% of        the porosity.

In some embodiments of the present invention, the osteobiologiccomponent of the present invention further comprises a gelled aqueousphase, wherein viable mesenchymnal stem cells are located in the aqueousphase.

Because mesenchymnal stem cells (and many growth factors) are very heatsensitive, it is desirable to deliver mesenchymnal stem cells and growthfactors at or near body temperature. However, many of the bioabsorbablepolymers are flowable at temperatures well in excess of bodytemperature. Similarly, many cross-linked polymers experience anexotherm of over 100° C. It is not known whether mesenchymnal stem cellsand growth factors could remain viable after prolonged exposure to thesetemperatures.

Since calcium phosphate can be made flowable at body temperature, it isdesirable to select an osteobiologic composition having a matrixcomprising calcium phosphate when also choosing to deliver themesenchymnal stem cells or growth factors to the disc space during thedelivery of the matrix component of the osteobiologic composition.

Therefore, in some embodiments there is provided an osteobiologiccomposition that is flowable at body temperature, the compositioncomprising a matrix comprising calcium phosphate and an osteogeniccomponent.

Hydrogels are useful in this respect because they can adequately protectbone growth cells contained therein.

A “hydrogel” is a substance formed when an organic polymer (natural orsynthetic) is set or solidified to create a three-dimensionalopen-lattice structure that entraps molecules of water or other solutionto form a gel. The solidification can occur, e.g., by aggregation,coagulation, hydrophobic interactions, or cross-linking. The hydrogelsemployed in this invention rapidly solidify to keep the cells at theapplication site, thereby eliminating problems of phagocytosis orcellular death and enhancing new cell growth at the application site.The hydrogels are also biocompatible, e.g., not toxic, to cellssuspended in the hydrogel.

A “hydrogel-cell composition” is a suspension of a hydrogel containingdesired tissue precursor cells. These cells can be isolated directlyfrom a tissue source or can be obtained from a cell culture. A “tissue”is a collection or aggregation of particular cells embedded within itsnatural matrix, wherein the natural matrix is produced by the particularliving cells.

The hydrogel-cell composition forms a uniform distribution of cells witha well-defined and precisely controllable density. Moreover, thehydrogel can support very large densities of cells, e.g., 50 millioncells/ml. These factors improve the quality and strength of the newtissue. In addition, the hydrogel allows diffusion of nutrients andwaste products to, and away from, the cells, which promotes tissuegrowth.

Hydrogels suitable for use in the osteobiologic composition of thepresent invention are water-containing gels, i.e., polymerscharacterized by hydrophilicity and insolubility in water. See, forinstance, “Hydrogels”, pages 458-459 in Concise Encyclopedia of PolymerScience and Engineering, Eds. Mark et al., Wiley and Sons, 1990, thedisclosure of which is incorporated herein by reference. Although theiruse is optional in the present invention, the inclusion of hydrogels ishighly preferred since they tend to contribute a number of desirablequalities. By virtue of their hydrophilic, water-containing nature,hydrogels generally can:

-   -   a) house mesenchymal stems cells,    -   b) assist the cured composite with load bearing capabilities of        the cured composite, and    -   c) decrease frictional forces on the composite and add thermal        elasticity.

Suitable hydrogels generally exhibit an optimal combination of suchproperties as compatibility with the matrix polymer of choice, andbiocompatibility.

Where the osteobiologic composition is delivered in conjunction with astrut and therefore is no longer required to bear the majority of loadson the spinal treatment site, the hydrogel phase is preferably betweenabout 50 and about 90 volume percent of the total volume, morepreferably between about 70 and about 85 volume percent.

In some embodiments wherein the osteobiologic component is a stand-alonecomponent (i.e., there is essentially no strut), the osetobiologiccomposition will preferably contain a hydrogel phase at a concentrationof between about 15 and 50 volume percent, and preferably between about20 and about 30 volume percent of the osteobiologic composition. Thelower levels of the hydrogel phase provide additional opportunity to usea strong matrix in the osteobiologic component.

Polymer-hydrogel composites demonstrate an optimal combination ofphysical/chemical properties, particularly in terms of theirconformational stability, resorption characteristics, biocompatibility,and physical performance, e.g., physical properties such as density,thickness, and surface roughness, and mechanical properties such asload-bearing strength, tensile strength, static shear strength, fatigueof the anchor points, impact absorption, wear characteristics, andsurface abrasion.

In general, an unsupported hydrogel is not sufficiently stiff or strongto survive the high spinal loads experienced during the fusion process.Accordingly, in many embodiments of the present invention, the hydrogelis supported not only by the strut component of the present invention,but also by the matrix component of the osteobiologic component. Inthese cases, the hydrogel is either delivered into the disc space alongwith the matrix component (as is preferred when the matrix component ofthe osteobiologic component comprises CaPO₄), or is delivered afterin-situ porosity has been produced in the matrix component of theosteobiologic component (as with flowable polymers).

However, in some embodiments, the strut component of the presentinvention may span a sufficiently large portion of the disc space andhave sufficient stiffness to adequately support and contain the hydrogelphase within the disc space without the need of a supplemental matrix inthe osetobiologic component. In these embodiments, the strut componentpreferably describes an arc of at least 200 degrees about the discspace, more preferably at least 270 degrees, more preferably at least350 degrees, and most preferably is about 360 degrees. Such struts areexemplified in FIGS. 2 (a) through (e), FIGS. 4 (a) and (b) and FIGS. 5(a) and (b).

Therefore, in accordance with the present invention, there is providedan intervertebral body fusion device, comprising:

-   -   a) an in situ produced load bearing strut having a shape that        spans at least 200 degrees, and    -   b) an osteobiologic component consisting essentially of:        -   an aqueous phase comprising an osteogenic component.

The hydrogel can include any of the following: polysaccharides,proteins, polyphosphazenes, poly(oxyethylene)-poly(oxypropylene) blockpolymers, poly(oxyethylene)-poly(oxypropylene) block polymers ofethylene diamine, poly(acrylic acids), poly(methacrylic acids),copolymers of acrylic acid and methacrylic acid, poly(vinyl acetate),and sulfonated polymers.

In general, these polymers are at least partially soluble in aqueoussolutions, e.g., water, or aqueous alcohol solutions that have chargedside groups, or a monovalent ionic salt thereof. There are many examplesof polymers with acidic side groups that can be reacted with cations,e.g., poly(phosphazenes), poly(acrylic acids), and poly(methacrylicacids). Examples of acidic groups include carboxylic acid groups,sulfonic acid groups, and halogenated (preferably fluorinated) alcoholgroups. Examples of polymers with basic side groups that can react withanions are poly(vinyl amines), poly(vinyl pyridine), and poly(vinylimidazole).

Water soluble polymers with charged side groups are cross-linked byreacting the polymer with an aqueous solution containing multivalentions of the opposite charge, either multivalent cations if the polymerhas acidic side groups, or multivalent anions if the polymer has basicside groups. Cations for cross-linking the polymers with acidic sidegroups to form a hydrogel include divalent and trivalent cations such ascopper, calcium, aluminum, magnesium, and strontium. Aqueous solutionsof the salts of these cations are added to the polymers to form soft,highly swollen hydrogels.

Anions for cross-linking the polymers to form a hydrogel includedivalent and trivalent anions such as low molecular weight dicarboxylateions, terepthalate ions, sulfate ions, and carbonate ions. Aqueoussolutions of the salts of these anions are added to the polymers to formsoft, highly swollen hydrogels, as described with respect to cations.

For purposes of preventing the passage of antibodies into the hydrogel,but allowing the entry of nutrients, a useful polymer size in thehydrogel is in the range of between 10,000 D and 18,500 D. Smallerpolymers result in gels of higher density with smaller pores.

Ionic polysaccharides, such as alginates or chitosan, can be used tosuspend living cells. In one example, the hydrogel is produced bycross-linking the anionic salt of alginic acid, a carbohydrate polymerisolated from seaweed, with ions, such as calcium cations. The strengthof the hydrogel increases with either increasing concentrations ofcalcium ions or alginate. For example, U.S. Pat. No. 4,352,883 describesthe ionic cross-linking of alginate with divalent cations, in water, atroom temperature, to form a hydrogel matrix.

Tissue precursor cells are mixed with an alginate solution, the solutionis delivered to an already implanted support structure and thensolidifies in a short time due to the presence in vivo of physiologicalconcentrations of calcium ions. Alternatively, the solution is deliveredto the support structure prior to implantation and solidified in anexternal solution containing calcium ions.

In some embodiments, the hydrogel comprises alginate. Alginate can begelled under mild conditions, allowing cell immobilization with littledamage. Binding of Mg²⁺ and monovalent ions to alginate does not inducegelation of alginate in aqueous solution. However, exposure of alginateto soluble calcium leads to a preferential binding of calcium andsubsequent gelling. These gentle gelling conditions are in contrast tothe large temperature or solvent changes typically required to inducesimilar phase changes in most materials.

Alginates have been utilized as immobilization matrices for cell, as aninjectable matrix for engineering cartilaginous tissue to treatvesicoureteral reflux in various animal models, and as injectablemicrocapsules containing islet cells to treat animal models of diabetes.

The open lattice structure and wide distribution of pore sizes incalcium alginate preclude the controlled release of large molecules(e.g., proteins) from these materials and limits the use of purealginate for entrapment of whole cells or cell organelles. However,alginate membrane can be modified by incorporating other polymericelements (e.g., lysine, poly(ethylene glycol), poly(vinyl alcohol) orchitosan). These modified systems have been used to control the releaseof proteins from alginate beads. Haemostatic swabs made of calciumalginate have also been clinically utilized to reduce blood loss duringsurgical procedures. The calcium ions in alginate may assist the bloodclotting process by activating platelets and clotting factor VII.

Collagen-polysaccharide-hydroxyapatite compositions suitable for amatrix of the present invention have been disclosed by Liu in U.S. Pat.No. 5,972,385, the entire teachings of which are incorporated herein byreference. A polysaccharide is reacted with an oxidizing agent to opensugar rings on the polysaccharide to form aldehyde groups. The aldehydegroups are reacted to form covalent linkages to collagen.

The type of polysaccharides which can be used include hyaluronic acid,chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan, heparansulfate, dextran, dextran sulfate, alginate, and other long chainpolysaccharides. In a preferred embodiment, the polysaccharide ishyaluronic acid.

A crosslinked collagen-polysaccharide matrix of the present inventionmay be used alone to conduct the growth of tissue; in combination with agrowth factor to induce the growth of tissue; in combination with fibrinto anchor the matrix into sites of tissue defect, or in combination withboth growth factor and fibrin.

The method of making a collagen-polysaccharide matrix of the presentinvention comprises the steps of oxidizing an exogenous polysaccharideto form a modified exogenous polysaccharide having aldehyde groups, andreacting the modified exogenous polysaccharide with collagen underconditions such that the aldehyde groups covalently react with collagento form a crosslinked matrix. The method may further comprise the stepof adding a growth factor to the matrix. A growth factor can be addedbefore or after the step of reacting the modified polysaccharide withthe collagen.

The fibrin used in a crosslinked collagen-polysaccharide matrix of thepresent invention is prepared by contacting a preformed matrix with asource of fibrinogen and thrombin or by combining the fibrinogen andthrombin with the modified exogenous polysaccharide and collagen at thetime of reaction. Alternately, fibrinogen and thrombin in a collagenpolysaccharide matrix may be added to another preformed collagenpolysaccharide matrix. Therefore, the present invention also comprises amethod for preparing a crosslinked collagen-polysaccharide matrixcomprising fibrin.

In other embodiments, the hydrogel comprises a microbial polysaccharide.Microbial polysaccharides are ubiquitous in nature and very abundantbiopolymers. They are of interest because of their unusual and usefulfunctional properties. Some of these properties are summarized asfollows: (i) film-forming and gel-forming capabilities, (ii) stabilityover broad temperature ranges, (iii) biocompatibility (natural productsavoid the release/leaching of toxic metals, residual chemicals,catalyst, or additives), (iv) unusual rheological properties, (v)biodegradability, (vi) water solubility in the native state or reducedsolubility if chemically modified, and (vii) thermal processability forsome of these polymers. It is worthy to note that gellan, one of themicrobial polysaccharides, has been investigated as immobilizationmaterials for enzymes and cells.

In some embodiments, the hydrogel is a synthetic hydrogel. One synthetichydrogel is polyphosphazene. Polyphosphazenes contain inorganicbackbones comprised of alternating single and double bonds betweennitrogen and phosphorus atoms, in contrast to the carbon-carbon backbonein most other polymers. The uniqueness of polyphosphazenes stems fromthe combination of this inorganic backbone with versatile side chainfunctionalities that can be tailored for different applications. Thedegradation of polyphosphazenes results in the release of phosphate andammonium ions along with the side groups.

Linear, uncross-linked polymers such as polyphosphazenes can be preparedby thermal ring opening polymerization of (NPCl₂)₃ and the chloro groupreplaced by amines, alkoxides or organometallic reagents to formhydrolytically stable, high molecular weight poly(organophosphazenes).Depending on the properties of the side groups, the polyphosphazenes canbe hydrophobic, hydrophilic or amphiphilic. The polymers can befabricated into films, membranes and hydrogels for biomedicalapplications by cross-linking or grafting. Bioerodible polymers for drugdelivery devices have been prepared by incorporating hydrolytic sidechains of imidazole for skeletal tissue regeneration.

Polyphosphazenes are polymers with backbones consisting of nitrogen andphosphorous atoms separated by alternating single and double bonds. Eachphosphorous atom is covalently bonded to two side chains.Polyphosphazenes that can be used have a majority of side chains thatare acidic and capable of forming salt bridges with di- or trivalentcations. Examples of acidic side chains are carboxylic acid groups andsulfonic acid groups.

Bioerodible polyphosphazenes have at least two differing types of sidechains, acidic side groups capable of forming salt bridges withmultivalent cations, and side groups that hydrolyze under in vivoconditions, e.g., imidazole groups, amino acid esters, glycerol, andglucosyl. Bioerodible or biodegradable polymers, i.e., polymers thatdissolve or degrade within a period that is acceptable in the desiredapplication (usually in vivo therapy), will degrade in less than aboutfive years and most preferably in less than about one year, once exposedto a physiological solution of pH 6-8 having a temperature of betweenabout 25° C. and 38° C. Hydrolysis of the side chain results in erosionof the polymer. Examples of hydrolyzing side chains are unsubstitutedand substituted imidizoles and amino acid esters in which the side chainis bonded to the phosphorous atom through an amino linkage.

Methods for synthesis and the analysis of various types ofpolyphosphazenes are described in U.S. Pat. Nos. 4,440,921, 4,495,174,and 4,880,622, the entire teachings of which are incorporated herein byreference. Methods for the synthesis of the other polymers describedabove are known to those skilled in the art. See, for example ConciseEncyclopedia of Polymer Science and Engineering, J. I. Kroschwitz,editor John Wiley and Sons, New York, N.Y., 1990, the entire teachingsof which are incorporated herein by reference. Many polymers, such aspoly(acrylic acid), alginates, and PLURONICS™, are commerciallyavailable.

Another synthetic hydrogel is poly(vinyl)alcohol (PVA). PVA is notsynthesized directly but is the deacetylated product of poly(vinylacetate). Polyvinyl acetate is usually prepared by radicalpolymerization of vinyl acetate (bulk, solution or emulsionpolymerizations). PVA is formed by either alcoholysis, hydrolysis oraminolysis processes of poly(vinyl acetate). The hydrophilicity andwater solubility of PVA can be readily controlled by the extent ofhydrolysis and molecular weight. PVA has been widely used as thickeningand wetting agent.

PVA gels can be prepared by cross-linking with formaldehyde in thepresence of sulfuric acid. These formaldehyde-cross-linked PVA materialshave been used as prosthesis for a variety of plastic surgeryapplications including breast augmentation, diaphragm replacement andbone replacement. However, a variety of complications were found afterlong term implantation, including calcification of the PVA.

More recently, PVA was made into an insoluble gel using a physicalcross-linking process. These gels were prepared with a repeatedfreezing-thawing process. This causes structural densification of thehydrogel due to the formation of semicrystalline structures. The use ofthis gel in drug delivery applications has been reported. However, PVAis not truly biodegradable due to the lack of labile bonds within thepolymer bond. Only low molecular weight materials are advisable to beused as implant materials.

Another synthetic hydrogel is polyethylene oxide (PEO). PEO can beproduced by the anionic or cationic polymerization of ethylene oxideusing a variety of initiators. PEO is highly hydrophilic andbiocompatible, and has been utilized in a variety of biomedicalapplications including preparation of biologically relevant conjugates,induction of cell membrane fusion and surface modification ofbiomaterials. Different polymer architectures have been synthesized andsome of their applications in medicine have been recently reviewed. Forexample, PEO can be made into hydrogels by γ-ray or electron beamirradiation and chemical crosslinking. These hydrogels have been used asmatrices for drug delivery and cell adhesion studies.

Pluronic polyols or polyoxamers are block copolymers of PEO andpoly(propylene oxide) and are usually synthesized by anionicpolymerization in the form of an ABA triblock using a difunctionalinitiator. Pluronics F 127, which contains 70% ethylene oxide and 30%propylene oxide by weight with an average molecular weight of 11,500, isthe most commonly used gel-forming polymer matrix to deliver proteins.

This polymer exhibits a reversible thermal gelation in aqueous solutionsat a concentration of 20% or more. Thus, the polymer solution is aliquid at room temperature but gels rapidly in the body. Although thepolymer is not degraded by the body, the gels dissolve slowly and thepolymer is eventually cleared. This polymer has been utilized in proteindelivery and skin burn treatments.

Although PGA is not water soluble, bioerodible hydrogels based onphotopolymerized PGA-PEO copolymers have been synthesized and theirbiological activities investigated. Macromonomers having a poly(ethyleneglycol) central block, extended with oligomers of .alpha.-hydroxy acids(e.g., oligo(dl-lactic acid) or oligo(glycolic acid)) and terminatedwith acrylate groups were synthesized. These hydrogels were designed toform direct contacts with tissues or proteins followingphotopolymerization, and act as a barrier.

These gels degrade upon hydrolysis of the oligo(α-hydroxy acid) regionsinto poly(ethylene glycol), the .alpha.-hydroxy acid, and oligo(acrylicacid). The degradation rate of these gels could be tailored from lessthan 1 day to 4 months by appropriate choice of theoligo(.alpha.-hydroxy acid). The macromonomer could be polymerized usingnon-toxic photoinitiators with visible light without excess heating orlocal toxicity. The hydrogels polymerized in contact with tissue adheretightly to the underlying tissue. In contrast, the gels were nonadhesiveif they were polymerized prior to contact with tissue. These hydrogelshave been utilized in animal models to prevent post-surgical adhesionand thrombosis of blood vessels and intimal thickening following ballooncatheterization.

It can thus be seen that there are a large number of syntheticbiodegradable polymers that may be used in the spinal tissue engineeringinvention described herein. Established polymer chemistries enable oneto tailor properties of the synthetic polymers by using different i)functional groups (either on the backbone or side chain), ii) polymerarchitectures (linear, branched, comb or star), and iii) combinations ofpolymer species physically mixed (polymer blends or interpenetratingnetworks) or chemically bonded (copolymers). The current preference forPGA and related polyesters is partially due to their established safetyin human applications, and the projected approval of the Food and DrugAdministration. PLGA can also be used with specific peptide sequencesincorporated into the polymer. Polymers constituted of building blockssimilar to components of ECM, e.g., carbohydrates and peptides, may alsobe used.

Other hydrogels that can be used in the methods of the invention aresolidified by either visible or ultraviolet light. These hydrogels aremade of macromers including a water soluble region, a biodegradableregion, and at least two polymerizable regions as described in U.S. Pat.No. 5,410,016, the entire teachings of which are incorporated herein byreference. For example, the hydrogel can begin with a biodegradable,polymerizable macromer including a core, an extension on each end of thecore, and an end cap on each extension. The core is a hydrophilicpolymer, the extensions are biodegradable polymers, and the end caps areoligomers capable of cross-linking the macromers upon exposure tovisible or ultraviolet light, e.g., long wavelength ultraviolet light.

Examples of such light solidified hydrogels include polyethylene oxideblock copolymers, polyethylene glycol polylactic acid copolymers withacrylate end groups, and 10 K polyethylene glycol-glycolide copolymercapped by an acrylate at both ends. As with the PLURONIC™ hydrogels, thecopolymers comprising these hydrogels can be manipulated by standardtechniques to modify their physical properties such as rate ofdegradation, differences in crystallinity, and degree of rigidity.

It is known that stem cells are fairly sensitive to temperatures greatlyin excess of body temperature. Therefore, in some embodiments of thepresent invention, the osteobiologic composition is delivered into thedisc space at a temperature of between about 37° C. and about 60° C.,preferably between about 40° C. and about 50° C., more preferablybetween about 40° C. and about 45° C.

In some embodiments, a semipermeable membrane is formed around thehydrogel to protect the cells inside. In these instances, the techniquesdisclosed in U.S. Pat. No. 4,352,883 by Lin, the entire teachings ofwhich are incorporated herein by reference (hereinafter “Lin”), areused.

In one aspect, the instant invention provides a method of encapsulatingbone growth cells or growth factors in a semipermeable membrane. Thebasic approach involves suspending the bone growth cells or growthfactors to be encapsulated in a physiologically compatible mediumcontaining a water-soluble substance that can be made insoluble inwater, that is, gelled, to provide a temporary protective environmentfor the tissue. The medium is next formed into droplets containing thebone growth cells or growth factors and gelled, for example, by changingconditions of temperature, pH, or ionic environment. The “temporarycapsules” thereby produced are then subjected to a treatment, which canbe a known treatment, that results in the production of membranes of acontrolled permeability (including impermeability) about theshape-retaining temporary capsules.

The temporary capsules can be fabricated from any nontoxic, watersoluble substance that can be gelled to form a shape retaining mass by achange of conditions in the medium in which it is placed, and also maycomprise plural groups that are readily ionized to form anionic orcationic groups. The presence of such groups in the polymer enablessurface layers of the capsule to be cross-linked to produce a“permanent” membrane when exposed to polymers containing multiplefunctionalities of the opposite charge.

The presently preferred material for forming the temporary capsules ispolysaccharide gums, either natural or synthetic, of the type which canbe (a) gelled to form a shape retaining mass by being exposed to achange in conditions such as a pH change or by being exposed tomultivalent cations such as Ca⁺⁺; and (b) permanently “crosslinked” orhardened by polymers containing reactive groups such as amine or iminegroups which can react with acidic polysaccharide constituents. Thepresently preferred gum is alkali metal alginate. Other water solublegums which may be used include guar gum, gum arabic, carrageenan,pectin, tragacanth gum, xanthan gum or acidic fractions thereof. Whenencapsulating thermally refractory materials, gelatin or agar may beused in place of the gums.

The preferred method of formation of the droplets is to force thegum-nutrient-tissue suspension through a vibrating capillary tube placedwithin the center of the vortex created by rapidly stirring a solutionof a multivalent cation. Droplets ejected from the tip of the capillaryimmediately contact the solution and gel as spheroidal shaped bodies.

The preferred method of forming a permanent semipermeable membrane aboutthe temporary capsules is to “crosslink” surface layers of a gelled gumof the type having free acid groups with polymers containing acidreactive groups such as amine or imine groups. This is typically done ina dilute solution of the selected polymer. Generally, the lower themolecular weight of the polymer, the greater the penetration into thesurface of the temporary capsule, and the greater the penetration, theless permeable the resulting membrane. Permanent crosslinks are producedas a consequence of salt formation between the acid reactive groups ofthe crosslinking polymer and the acid groups of the polysaccharide gum.Within limits, semipermeability can be controlled by setting themolecular weight of the crosslinking polymer, its concentration, and theduration of reaction. Crosslinking polymers which have been used withsuccess include polyethylenimine and polylysine. Molecular weight canvary, depending on the degree of permeability required, between about3,000 and about 100,000 or more. Good results have been obtained usingpolymers having an average molecular weight on the order of about35,000.

The capsules can be engineered to have a selected in vivo useful life byastute selection of the cross-linking polymer. Proteins or polypeptidecrosslinkers, e.g., polylysine, are readily attached in vivo resultingin relatively rapid destruction of the membrane. Cross-linkers notreadily degradable in mammalian bodies, e.g., polyethyleneimine, resultin longer lasting membranes. By selecting the crosslinking polymer or bycross-linking simultaneously or sequentially with two or more suchmaterials, it is possible to preselect the length of time the implantedtissue remains protected.

Optionally, with certain materials used to form the temporary capsules,it is possible to improve mass transfer within the capsule afterformation of the permanent membrane by re-establishing the conditionsunder which the material is liquid, e.g., removing the multivalentcation. This can be done by ion exchange, e.g., immersion in phosphatebuffered saline or citrate buffer. In some situations, such as where itis desired to preserve the encapsulated tissue, or where the temporarygelled capsule is permeable, it may be preferable to leave theencapsulated gum in the crosslinked, gelled state.

An alternative method of membrane formation involves an interfacialpolycondensation of polyaddition. This approach involves preparing asuspension of temporary capsules in an aqueous solution of the watersoluble reactant of a pair of complementary monomers which can form apolymer. Thereafter, the aqueous phase is suspended in a hydrophobicliquid in which the complementary reactant is soluble. When the secondreactant is added to the two-phase system, polymerization takes place atthe interface. Permeability can be controlled by controlling the makeupof the hydrophobic solvent and the concentration of the reactants. Stillanother way to form a semipermeable membrane is to include a quantity ofprotein in the temporary capsule which can thereafter be crosslinked insurface layers by exposure to a solution of a crosslinking agent such asgluteraldehyde.

The foregoing process has been used to encapsulate viable mesenchymalstems cells which, in a medium containing the nutrients and othermaterials necessary to maintain viability and support in vitrometabolism of the tissue, provide bone growth.

In another aspect, the instant invention provides a tissue implantationmethod which does not require surgery and which overcomes many of theproblems of immune rejection. In accordance with the invention, thecapsules are injected into a suitable site in a mammalian body, andfunction normally until the tissue expires, or until natural bodyprocesses succeed in isolating the capsules so that substances requiredfor viability of the tissue are no longer available. At this point,because surgery is not required for the implant, fresh tissue may bereadily provided by another injection. The mammalian body mayaccordingly be provided with the specialized function of the tissue aslong as desired.

In a preferred embodiment of the invention, mammalian mesenchymal stemscells are encapsulated in polylysine and polyethyleneimine cross-linkedalginate membranes. These may be injected into the polymer matrix of theosteobiologic component.

Accordingly, it is a primary object of the invention to provide a methodof encapsulating living a osteogenic component or growth factors withina membrane permeable to the nutrients and other substances needed formaintenance and metabolism and to metabolic products, but impermeable tothe polymer matrix material having a molecular weight above a selectedlevel.

Other objects of the invention are to provide a method of implantingliving tissue in mammalian bodies and to provide a non-surgical tissueimplantation technique. Still another object is to provide a method ofencapsulating living tissue which allows the production of capsuleshaving a high surface area to volume ratio and membranes with apreselected in vivo residence time.

Each of IPNs and S-IPNs are extremely desirable because cells can besuspended in the polymer solutions which can be cross-linked by anon-toxic active species, such as by photoinitiation. In someembodiments, both the active species, and the initiator are present inan amount that is non-toxic to cells. In other embodiments, the activespecies is present in an amount that is non-toxic to cells and theinitiation occurs via photoinitiation.

Cells can be obtained directed from a donor, from cell culture of cellsfrom a donor, or from established cell culture lines. In the preferredembodiments, cells are obtained directly from a donor, washed andimplanted directly in combination with the polymeric material. The cellsare cultured using techniques known to those skilled in the art oftissue culture.

Cell attachment and viability can be assessed using scanning electronmicroscopy, histology, and quantitative assessment with radioisotopes.The function of the implanted cells can be determined using acombination of the above-techniques and functional assays. For example,in the case of hepatocytes, in vivo liver function studies can beperformed by placing a cannula into the recipient's common bile duct.Bile can then be collected in increments. Bile pigments can be analyzedby high pressure liquid chromatography looking for underivatizedtetrapyrroles or by thin layer chromatography after being converted toazodipyrroles by reaction with diazotized azodipyrrolesethylanthranilate either with or without treatment with P-glucuronidase.Diconjugated and monoconjugated bilirubin can also be determined by thinlayer chromatography after alkalinemethanolysis of conjugated bilepigments. In general, as the number of functioning transplantedhepatocytes increases, the levels of conjugated bilirubin will increase.Simple liver function tests can also be done on blood samples, such asalbumin production. Analogous organ function studies can be conductedusing techniques known to those skilled in the art, as required todetermine the extent of cell function after implantation. For example,islet cells of the pancreas may be delivered in a similar fashion tothat specifically used to implant hepatocytes, to achieve glucoseregulation by appropriate secretion of insulin to cure diabetes. Otherendocrine tissues can also be implanted. Studies using labeled glucoseas well as studies using protein assays can be performed to quantitatecell mass on the polymer scaffolds. These studies of cell mass can thenbe correlated with cell functional studies to determine what theappropriate cell mass is. In the case of chondrocytes, function isdefined as providing appropriate structural support for the surroundingattached tissues.

This technique can be used to provide multiple cell types, includinggenetically altered cells, within a three-dimensional scaffolding forthe efficient transfer of large number of cells and the promotion oftransplant engraftment for the purpose of creating a new tissue ortissue equivalent. It can also be used for immunoprotection of celltransplants while a new tissue or tissue equivalent is growing byexcluding the host immune system.

Examples of cells which can be implanted as described herein includechondrocytes and other cells that form cartilage, osteoblasts and othercells that form bone, muscle cells, fibroblasts, and organ cells. Asused herein, “organ cells” includes hepatocytes, islet cells, cells ofintestinal origin, cells derived from the kidney, and other cells actingprimarily to synthesize and secret, or to metabolize materials.

In some embodiments, the osteobiologic component comprises anosteoconductive phase. In some embodiments, the osteoconductive phasecomprises a particulate phase comprising a hard tissue, osteoconductiveor osteoinductive calcium containing, non-fibrous, powdered compound,wherein the calcium containing compound comprises a material having theformula:

M²⁺ _((10-n))N¹⁺ _(2n)(ZO₄ ³⁻)₆ mY^(x−)

where n=1-10, and m=2 when x=1, and/or m=1 when x=2where M and N are alkali or alkaline earth metals, preferably calcium,magnesium, sodium, zinc and potassium. ZO₄ is an acid radical, where Zis preferably phosphorus, arsenic, vanadium, sulfur or silicon, or issubstituted in whole or part with carbonate (CO₃ ²⁻. Y is an anion,preferably halide, hydroxide, or carbonate.

Most preferably, the calcium containing compound comprises mono-, di-,octa-, .alpha.-tri-, .beta.-tri-, or tetra-calcium phosphate,hydroxyapatite, fluorapatite, calcium sulfate, calcium fluoride andmixtures thereof.

The calcium containing bone regenerating compound can also contain abioactive glass comprising metal oxides such as calcium oxide, silicondioxide, sodium oxide, phosphorus pentoxide, and mixtures thereof, andthe like.

Preferably, the calcium containing compound used in the composites ofthe present invention will have a particle size of about 10 microns toabout 1000 microns, and most preferably about 100 microns to about 500microns. The particles are prepared by conventional processes such aspulverizing, milling, and the like.

In some embodiments, hydroxyapatite particles are preferably the type ofdry free-flowing hydroxyapatite particles supplied for use in formingwetted, loose-mass implants, and can be obtained commercially fromOrthomatrix Corporation (Dublin, Calif.) or Calcitek (San Diego,Calif.). Particle sizes of between about 250 and 2000 microns arepreferred, smaller particles showing increased difficulty in allowingtissue ingrowth and larger particles requiring increased quantities ofbinder for ease of application.

In some embodiments, the material comprising the osteobiologic componentof the present invention has at least one of the following intrinsicproperties:

Intrinsic Property Preferred Value More Preferred Value CompressionStrength >1 MPa >10 MPa Fracture Strength >1 MPa >10 MPa CompressionModulus 0.1-2 GPa 0.2-0.7 GPa

In some embodiments, the osteobiologic component of the presentinvention has the following mechanical performance characteristics:

Mechanical Property Preferred Value More Preferred Value StaticCompressive Load >2 kN >4 kN

One example of such an osteobiologic composition comprises an in situformed, porous, polyoxaester scaffold that occupies the space created bythe strut described in FIGS. 2 (f) and 2 (g).

In some embodiments, the polymer has a Tm of no more than about 80° C.This allows the use of water or steam as the heating fluid. In someembodiments, the polymer has a Tm of less than 100° C., and so is lesslikely to damage surrounding tissue.

In particular, preferred embodiments, in the solidified form, exhibitmechanical properties approximating those of the cancellous bone. Forinstance, preferred embodiments of the osetobiologic composition exhibita load bearing strength of between about 50 and about 200 psi (poundsper square inch), and preferably between about 100 and about 150 psi.Such composites also exhibit a shear stress of between about 10 and 100psi, and preferably between about 30 and 50 psi, as such units aretypically determined in the evaluation of natural tissue and joints.

As used herein, the term “growth factors” encompasses any cellularproduct that modulates the growth or differentiation of other cells,particularly connective tissue progenitor cells. The growth factors thatmay be used in accordance with the present invention include, but arenot limited to, FGF-1, FGF-2, FGF-4, PDGFs, EGFs, IGFs, PDGF-bb, bonemorphogenetic protein-1, bone morphogenetic protein-2, OP-1,transforming growth factor-13, osteoid-inducing factor (OIF),angiogenin(s), endothelins, hepatocyte growth factor and keratinocytegrowth factor, osteogenin (bone morphogenetic protein-3); bonemorphogenetic protein-2; OP-1; bone morphogenetic protein-2A, -2B, and-7; transforming growth factor-β, HBGF-1 and -2; isoforms ofplatelet-derived growth factors (PDGF), fibroblast growth factors,epithelial growth factors, isoforms of transforming growth factor-β,insulin-like growth factors, and bone morphogenic proteins, and FGF-1and 4.

Growth factors which can be used with a matrix of the present inventioninclude, but are not limited to, members of the transforming growthfactor-β superfamily, including transforming growth factor-β1, 2 and 3,the bone morphogenetic proteins (BMP's), the growth differentiationfactors (GDF's), and ADMP-1; members of the fibroblast growth factorfamily, including acidic and basic fibroblast growth factor (FGF-1 and-2); members of the hedgehog family of proteins, including indian, sonicand desert hedgehog; members of the insulin-like growth factor (IGF)family, including IGF-I and -II; members of the platelet-derived growthfactor (PDGF) family, including PDGF-AB, PDGF-BB and PDGF-AA; members ofthe interleukin (IL) family, including IL-1 thru -6; and members of thecolony-stimulating factor (CSF) family, including CSF-1, G-CSF, andGM-CSF.

As noted above, there is a concern that including osteogenic componentsand osteoinductive components in a heated polymer matrix may rendernonviable or denature these components. However, there are some growthfactors known to those skilled in the art that are more heat resistantthan the majority of growth factors. It is believed that these hightemperature growth factors in osteobiologic compositions may be includedin osteobiologic compositions that are to be flowed into the disc spaceat temperatures between body temperature and about 45° C.

Accordingly, in one embodiment, the present invention is apharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent and (a) at least one polymer flowable between 38° C.and 45° C. selected from the group consisting of homopolymers ofpoly(ε-caprolactone), poly(p-dioxanone), or poly(trimethylene carbonate)or copolymers or mixtures thereof, or copolyesters of p-dioxanone ortrimethylene carbonate and glycolide or lactide or mixtures thereof, andin particular, copolymers of p-dioxanone/glycolide, p-dioxanone/lactide,trimethylene carbonate/glycolide and trimethylene carbonate/lactide, orcopolyesters of .epsilon.-caprolactone and glycolide or mixturesthereof, or mixtures of homopolymers of ε-caprolactone and lactide, and(b) at least one growth factor resistant to denaturing at at least about45° C. selected from the group consisting of bone morphogeneticproteins.

As used herein, a “pharmaceutical composition” is a formulationcomprising the disclosed compounds and a pharmaceutically acceptablediluent or carrier, in a form suitable for administration to a subject.The quantity of active ingredient (e.g. a growth factor) in a unit doseof composition is an effective amount and may be varied according to theparticular treatment involved. As used herein, an “effective amount” ofa compound is the quantity which, when administered to a subject in needof treatment, improves the prognosis of the subject, e.g. reduces theseverity of one or more of the subject's symptoms associated with aspinal injury. It may be appreciated that it may be necessary to makeroutine variations to the dosage depending on the age and condition ofthe patient. The amount of the active ingredient to be administered to asubject will depend on the type of injury and the characteristics of thesubject, such as general health, other diseases, age, sex, genotype,body weight and tolerance to drugs. The skilled artisan will be able todetermine appropriate dosages depending on these and other factors.

The compounds described herein can be used in pharmaceuticalpreparations in combination with a pharmaceutically acceptable carrieror diluent. Suitable pharmaceutically acceptable carriers include inertsolid fillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein. Techniques for formulation and administration of the compoundsof the instant invention can be found in Remington: the Science andPractice of Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa.(1995).

Preferably, the matrix material becomes flowable in the temperaturerange of at least 40° C. and 55° C., more preferably in the temperaturerange of at least 45° C. and 50° C.

Preferably, the growth factor is resistant to denaturing at atemperature of at least 40° C. In some embodiments, the growth factor isa dimer. In some embodiments, the growth factor is a bone morphogeneticprotein dimer.

If desired, substances such as antibiotics, antibacterial agents, andantifungal agents may also be admixed with the polymer. Examples ofantimicrobial agents which may be employed include tetracycline,oxytetracycline, chlorotetracycline, neomycin, erithromycin, and itsderivative, bacitracin, streptomycin, rifampicin and its derivativessuch as N-dimethylrifampicin, kanamycin and chloromycetin. Usefulantifungal agents include griseofulvin, mycostatin, miconazole and itsderivatives as described in U.S. Pat. No. 3,717,655, the entireteachings of which are incorporated herein by reference; bisdiguanidessuch as chlorhexidine; and more particularly quaternary ammoniumcompounds such as domiphen bromide, domiphen chloride, domiphenfluoride, benzalkonium chloride, cetyl pyridinium chloride, dequaliniumchloride, the cis isomer of1-(3-chlorallyl)-3,5,7-triaza-1-azoniaadamantane chloride (availablecommercially from the Dow Chemical Company under the trademark Dowicil200) and its analogues as described in U.S. Pat. No. 3,228,828, theentire teachings of which are incorporated herein by reference, cetyltrimethyl ammonium bromide as well as benzethonium chloride andmethylbenzethonium chloride such as described in U.S. Pat. Nos.2,170,111, 2,115,250 and 2,229,024, the entire teachings of which areincorporated herein by reference; the carbanilides and salicylanilidessuch 3,4,4′-trichlorocarbanilide, and 3,4′5-tribromosalicylanilide; thehydroxydiphenyls such as dichlorophene, tetrachlorophene,hexachlorophene, and 2,4,4′-trichloro-2′-hydroxydiphenylether; andorganometallic and halogen antiseptics such as sinc pyrithione, silversulfadiazone, silver uracil, iodine, and the iodophores derived fromnon-ionic surface active agents such as are described in U.S. Pat. Nos.2,710,277 and 2,977,315, the entire teachings of which are incorporatedherein by reference, and from polyvinylpyrrolidone such as described inU.S. Pat. Nos. 2,706,701, 2,826,532 and 2,900,305, the entire teachingsof which are incorporated herein by reference.

Optionally, the matrix has antibodies that have affinity for connectivetissue progenitor stem cells bound to the surface thereof. Suitableantibodies, include by way of example, STRO-1, SH-2, SH-3, SH-4, SB-10,SB-20, and antibodies to alkaline phosphatase. Such antibodies aredescribed in Haynesworth et al., Bone (1992), 13:69-80; Bruder, S. etal., Trans Ortho Res Soc (1996), 21:574; Haynesworth, S. E., et al.,Bone (1992), 13:69-80; Stewart, K., et al, J Bone Miner Res (1996),11(Suppl.):S142; Flemming J E, et al., in “Embryonic Human Skin.Developmental Dynamics,” 212:119-132, (1998); and Bruder S P, et al.,Bone (1997), 21(3): 225-235, the entire teachings of which areincorporated herein by reference.

In U.S. Pat. No. 6,197,325, the entire teachings of which areincorporated herein by reference, Mac Phee discloses that drugs,polyclonal and monoclonal antibodies and other compounds, including, butnot limited to, DBM and bone morphogenetic proteins may be added to thematrix, such as a matrix of the present invention. They accelerate woundhealing, combat infection, neoplasia, and/or other disease processes,mediate or enhance the activity of the growth factor in the matrix,and/or interfere with matrix components which inhibit the activities ofthe growth factor in the matrix. These drugs may include, but are notlimited to: antibiotics, such as tetracycline and ciprofloxacin;antiproliferative/cytotoxic drugs, such as 5-fluorouracil (5-FU), taxoland/or taxotere; antivirals, such as gangcyclovir, zidovudine,amantidine, vidarabine, ribaravin, trifluridine, acyclovir,dideoxyuridine and antibodies to viral components or gene products;cytokines, such as α- or β- or γ-Interferon, α- or β-tumor necrosisfactor, and interleukins; colony stimulating factors; erythropoietin;antifungals, such as diflucan, ketaconizole and nystatin; antiparasiticagents, such as pentamidine; anti-inflammatory agents, such asα-1-anti-trypsin and α-1-antichymotrypsin; steroids; anesthetics;analgesics; and hormones. Other compounds which may be added to thematrix include, but are not limited to: vitamins and other nutritionalsupplements; hormones; glycoproteins; fibronectin; peptides andproteins; carbohydrates (both simple and/or complex); proteoglycans;antiangiogenins; antigens; oligonucleotides (sense and/or antisense DNAand/or RNA); bone morphogenetic proteins; DBM; antibodies (for example,to infectious agents, tumors, drugs or hormones); and gene therapyreagents. Genetically altered cells and/or other cells may also beincluded in the matrix of this invention.

If desired, substances such as pain killers and narcotics may also beadmixed with the polymer for delivery and release to the disc space.

In some embodiments of the resent invention, the additive is embeddedwithin the matrix material of the scaffold. In other embodiments, theadditive resides on the inner surface of the open porosity created bythe leaching of the leachate. In other embodiments, the additive resideswithin the hydrogel phase.

When the osteobiologic composition comprises one or more bonemorphogenetic proteins, they are preferably located on the inner surfaceof the open porosity in the case where the scaffold is formed prior tobeing populated with cells, and are preferably located within thehydrogel phase in the case where a hydrogel is used to deliver cells atthe same time the scaffold is delivered. This is done so that the cellswill contact the bone morphogenetic proteins as soon as possiblefollowing implantation in order to initiate the bone forming process.Furthermore, since the bone morphogenetic proteins have a limited timein which they are active in inducing cells to form bone, it is importantto expose the cells to the bone morphogenetic proteins as soon aspossible to take maximum advantage of their potency.

When osteoprogenitor cells are seeded onto the scaffold following insitu formation of the scaffold, they preferably adhere to the surface ofthe inner porosity of the scaffold. This is important becauseosteoprogenitor cells must attach to a substrate in order to beginforming bone. Likewise when osteoprogenitor cells are delivered to thefusion site while encapsulated in a hydrogel, they preferably attach tothe inner porosity of the hydrogel.

In some embodiments, bone morphogenetic protein is present in thescaffold in a concentration of at least 2 times the atologusconcentration. More preferably, the bone morphogenetic protein ispresent in the scaffold in a concentration of at least 100 times theautologous concentration.

In some embodiments, mesenchymnal stem cells are present in the scaffoldin a concentration of at least 2 times the autologous concentration.More preferably the mesenchymnal stem cells are present in thescaffolding in a concentration of 10 times the autologous concentration,and most preferably they are present in a concentration of 100 times theautologous concentration.

In some embodiments, the osteobiologic composition has a sufficientlyhigh osteobiologic nature and a matrix that is sufficiently resistant todegradation that the bone growth essentially fills the entire porosityof the scaffold of the osteobiologic composition before there is anysignificant degradation of the matrix. In such a case, the new bone canbegin to significantly share the compressive load experienced by thedevice before the device undergoes a significant loss in strength.

In preferred embodiments, bony ingrowth penetrates at least 50% of thedistance to the center of the implant before the matrix loses 50% of itsweight. In more preferred embodiments, bony ingrowth penetrates at least75% of the distance to the center of the implant before the matrix loses25% of its weight. In more preferred embodiments, bony ingrowthpenetrates at least 90% of the distance to the center of the implantbefore the matrix loses 10% of its weight.

In preferred embodiments, bony ingrowth penetrates at least 50% of thedistance to the center of the implant before the matrix loses 50% of itscompressive strength. In more preferred embodiments, bony ingrowthpenetrates at least 75% of the distance to the center of the implantbefore the matrix loses 25% of its compressive strength. In morepreferred embodiments, bony ingrowth penetrates at least 90% of thedistance to the center of the implant before the matrix loses 10% of itscompressive strength.

In accord with the present invention, the injectable implants of theinvention can be used to fuse facets and to fuse the interspinousregion. In some embodiments, the implants of the present invention usean elastomer to tension the interspinous region to correct lordoticangle.

It is further believed that the above noted osteobiologic compositionscan be advantageously used in vertebroplasty procedures, particularlywhen delivered into the porosity of a skeleton created in the vertebralbody, as disclosed in U.S. patent application by Martin Reynoldsentitled “Method of Performing Embolism Free Vertebroplasty and DeviseTherefore,” which was filed on Nov. 21, 2002, the entire teachings ofwhich are incorporated herein by reference.

Additional Embodiments

In one embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space. The devicecomprises a strut. The strut includes an upper surface for bearingagainst the upper endplate, a lower surface for bearing against thelower endplate, and an in-situ formed load bearing composition disposedbetween the upper and lower surfaces.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut, having a shape memory, and an in-situ formedosteobiologic component. The strut further includes (i) an upper surfacefor bearing against the upper endplate and (ii) a lower surface forbearing against the lower endplate.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut and an in-situ formed osteobiologic component.The strut includes an upper surface for bearing against the upperendplate, and a lower surface for bearing against the lower endplate.The in-situ formed osteobiologic component includes a matrix componenthaving an internal surface defining a scaffold having open porositysuitable for bone growth therethrough, and an osteogenic componentlocated within the open porosity.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut and an in-situ formed osteobiologic component.The strut includes an upper surface for bearing against the upperendplate, and a lower surface for bearing against the lower endplate.The in-situ formed osteobiologic component includes an injectable matrixcomponent, and an osteoinductive component embedded within the matrix.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut and an in-situ formed osteobiologic component.The strut includes an upper surface for bearing against the upperendplate, and a lower surface for bearing against the lower endplate.The in-situ formed osteobiologic component includes an injectable matrixcomponent, and a porogen embedded within the matrix.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut and an in-situ formed osteobiologic component.The strut includes an upper surface for bearing against the upperendplate, and a lower surface for bearing against the lower endplate.The in-situ formed osteobiologic component includes an expandable devicedefining a cavity, and an injectable osteobiologic composition locatedwithin the cavity.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut that includes an expandable device having acavity, an upper surface for bearing against the upper endplate, a lowersurface for bearing against the lower endplate, and an inner walldefining a through hole. The strut further includes an injectable loadbearing composition located within the cavity. The fusion device furtherincludes an osteobiologic component located in the throughhole.

In another embodiment, the present invention is an intervertebral fusiondevice comprising a strut and an in-situ formed osteobiologic component.The strut includes an upper surface for bearing against the upperendplate a lower surface for bearing against the lower endplate.Preferably, the in-situ formed osteobiologic component includes aninjectable, matrix component essentially free of monomer.

In another embodiment, the present invention is an intervertebral fusiondevice for providing bony fusion across a disc space, comprising astrut. The strut includes an upper surface for bearing against the upperendplate, a lower surface for bearing against the lower endplate, and anin-situ formed load bearing composition disposed between the upper andlower surfaces and made of a material comprising a cross-linkedresorbable polymer.

The Preferred Embodiments

As used herein, the term “toroid” refers to a surface obtained by atleast partially rotating a closed curve, which lies in a plane, about anaxis parallel to the plane and which does not intersect the curve. Anexample of an “open cavity defined by an outer surface of a toroid” is ahole.

In one preferred embodiment, the present invention is an intervertebralspinal fusion device comprising at least one arcuate inflatable balloonthat upon expansion between two adjacent vertebrae at least partiallyrestores natural a natural angle between two adjacent vertebrae, saiddevice having a footprint that substantially corresponds to a perimeterof a vertebral endplate.

Preferably, the intervertebral spinal fusion device has an upper area, alower area, an anterior area and a posterior area. Upon inflation, saiddevice can have a footprint that substantially corresponds to a rim of avertebral endplate and said anterior area height being greater than saidposterior area height. More preferably, upon expansion, at least aportion of the device has a generally toroidal shape thereby defining anopen cavity having an axial dimension and a radial dimension. In oneembodiment, the device comprises at least one expandable balloon thatcontains a plurality of lumena.

In a particularly preferred embodiment, the device comprises at leastone said balloon including a resorbable, semi-permeable materialselected from the group consisting of polyolefin copolymers,polyethylene, polycarbonate, polyethylene terephthalate, ether-ketonepolymers, woven fibers, nonwoven fibers, fabrics and metal mesh.

In a preferred embodiment, the balloon defines at least one opening.

In another embodimemt, the upper and lower areas of the device have aplurality of outward projections. The outward projections preferablyinclude polyetherether ketone (PEEK).

The upper area of the device can include at least one material selectedfrom the group consisting of polyether block copolymer (PEBAX), ABS(acrylonitrile butadiene styrene), ANS (acrylonitrile styrene), delrinacetal; PVC (polyvinyl chloride), PEN (polyethylene napthalate), PBT(polybutylene terephthalate), polycarbonate, PEI (polyetherimide), PES(polyether sulfone), PET (polyethylene terephthalate), PETG(polyethylene terephthalate glycol), polyamide, aromatic polyamide,polyether, polyester, polymethylmethacrylate, polyurethane copolymer,ethylene vinyl acetate (EVA), ethylene vinyl alcohol, polyethylene,latex rubber, FEP (fluorinated ethylene polymer), PTFE(polytetrafluoroethylene), PFA (perfluoro-alkoxyalkane), polypropylene,polyolefin, polysiloxane, liquid crystal polymer, ionomer,poly(ethylene-co-methacrylic) acid, silicone rubber, SAN (styreneacrylonitrile), nylon, polyether block amide and thermoplasticelastomer.

In one preferred embodiment, the device of the present invention has atleast one balloon that contains at least one member of the groupconsisting of a load-bearing component and an osteobiologic component.The load-bearing and the osteobiologic components can be used alone orin combination. Combination is preferred. In a particularly preferredembodiment, the load-bearing and the osteobiological components areresorbable.

The load-bearing component can comprise at least one compound selectedfrom the group consisting of poly(lactic acid), poly(glycolic acid),p-dioxanone fibers, polyarylethyl, polymethylmethacrylate, polyurethane,amino-acid-derived polycarbonate, polycaprolactone, aliphaticpolyesters, calcium phosphate, unsaturated linear polyesters, vinylpyrrolidone and polypropylene fumarate diacrylate, or mixtures thereof.

The osteobiologic component can include at least one element selectedfrom the group consisting of mesenchymal stem cells, growth factors,cancellous bone chips, hydroxyapatite, tri-calcium phosphate, polylacticacid, polyglycolic acid, polygalactic acid, polycaprolactone,polyethylene oxide, polypropylene oxide, polysulfone, polyethylene,polypropylene, hyaluronic acid, bioglass, gelatin, collagen and choppedpolymeric fibers or mixtures thereof.

As used herein, the term “cancellous” refers to a bone having a porousstructure. The normal type of adult mammalian bone, whether cancellousor compact, is composed of parallel lamellae in the former andconcentric lamellae in the latter; lamellar organization reflects arepeating pattern of collagen fibroarchitecture. Adult bone consistingof mineralised regularly ordered parallel collagen fibres more looselyorganised than the lamellar bone of the shaft of adult long bones, suchas bone found in the end of long bones, is known as “cancellous bone”.

In another preferred embodiment, the device can further comprise anosteoinductive component and an osteoconductive component.

The osteoinductive component can include at least one compound selectedfrom the group consisting of fibroblast growth factors, such as (FGFs)FGF-1, FGF-2 and FGF-4; platelet-derived growth factors (PDGFs), such asPDGF-AB, PDGF-BB, PDGF-AA; epithelial growth factors EGFs; insulin-likegrowth factors (IGF), such as IGF-I, IGF-II; osteogenic protein-1(OP-1); transforming growth factors (TGFs), such as transforming growthfactor-β, transforming growth factor-β1, transforming growth factor-β2,transforming growth factor-β3; osteoid-inducing factor (OIF);angiogenin(s); endothelins; hepatocyte growth factor and keratinocytegrowth factor; bone morphogenetic proteins (BMPs), such as osteogenin(bone morphogenetic protein-3), bone morphogenetic protein-2; bonemorphogenetic protein-2A, bone morphogenetic protein-2B, bonemorphogenetic protein-7; heparin-binding growth factors (HBGFs), such asHBGF-1, HBGF-2; isoforms of platelet-derived growth factors, fibroblastgrowth factors, epithelial growth factors transforming growth factor-β,insulin-like growth factors, bone morphogenic proteins, the bonemorphogenetic proteins and the growth differentiation factors (GDF's);Indian hedgehog, sonic hedgehog, desert hedgehog; cytokines, such asIL-1, IL-2, IL-3, IL-4, IL-5, IL-6; colony-stimulating factors (CSFs),such as CSF-1, G-CSF and GM-CSF or mixtures thereof.

The osteoconductive component can include at least one compound selectedfrom the group consisting of a material having the formula:

M²⁺ _((10-n))N¹⁺ _(2n)(ZO₄ ³⁻)₆ mY^(x)

wheren=1-10, and m=2 when x=1, and/or m=1 when x=2;M and N are alkali or alkaline earth metals;ZO₄ is an acid radical, where Z is phosphorus, arsenic, vanadium, sulfuror silicon; andY is an anion, preferably halide, hydroxide, or carbonate.

The osteoconductive component can further include at least one ofmaterial selected from the group consisting of mono-calcium phosphate,di-calcium phosphate, octa-calcium phosphate, alpha-tri-calciumphosphate, beta-tri-calcium phosphate, or tetra-calcium phosphate,hydroxyapatite, fluorapatite, calcium sulfate, calcium fluoride, calciumoxide, silicon dioxide, sodium oxide, and phosphorus pentoxide ormixtures thereof.

In another preferred embodiment, the osteobiologic component can furtherinclude at least one water-soluble materials selected from the groupconsisting of gelatin, salts, polysaccharides and proteins.

A particularly preferred embodiment of the present invention is anintervertebral spinal fusion device shown in FIGS. 17 (a) (collapsed)and (b) (expanded). The device 100 comprises (a) a partially rigidanterior frame 110 detachably connected to a first fluid communicationmeans 120, said frame having an upper inflatable rim 130 and a lowerinflatable rim 140; and (b) a rigid posterior expandable frame 150,detachably connected to a second fluid communication means 122, saidframe having a rigid upper rim 160 and a rigid lower rim 170, connectedrespectively to the upper inflatable rim 130 and lower inflatable rim140 of the anterior frame 110.

Preferably, the device further comprises at least one mesh element 180connected to the upper and the lower inflatable rims 130 and 140 of theanterior frame 110. At least one of the upper and the lower inflatablerims 130 and 140 of the anterior frame 110 of the device 100 can have aplurality of outward projections 190.

Most preferably, the posterior frame 150 of the device further includesat least one telescopically expandable supporting element 200, each saidsupporting element being connected to the upper and the lower rigid rims160 and 170 of the posterior frame 150.

Device 100 can be inserted into an intervertebral space in a collapsedstate 210. Device 100 can next be oriented so that the anterior frame110 of the device is oriented to face an anterior aspect of a vertebra,the posterior frame 150 of the device is oriented to face a posterioraspect of the vertebra and the upper and lower rims 130, 140, 160 and170 of each frame face upper and lower vertebral endplates endplates,respectively.

In a preferred embodiment, at least one of the load-bearing componentand the osteobiologic component is directed into the device by directingat least one component under pressure through at least one of the firstand the second fluid communication means 120 and 122, thereby causingthe device to expand and directing the upper inflatable rim 130 and thelower inflatable rim 140 of the anterior frame and a posterior frame 150of the device against the respective vertebral endplates, thereby atleast partially restoring a natural angle between two adjacentvertebrae.

In a particularly preferred embodiment, upon at least partially fillingthe upper and lower inflatable rims 130 and 140 and the posterior frame150 between two adjacent vertebrae (not shown), natural angle betweensaid two vertebrae is at least partially restored. Preferably, uponfilling the upper and the lower inflatable rims 130 and 140 and theposterior frame 150, the distance D between the upper and the lowerinflatable rims is different from the height h of the posterior frame.In one embodiment, upon at least partially filling the upper and thelower inflatable rims 130 and 140, said rims each have a footprintsubstantially corresponding to a rim of a vertebral endplate.Preferably, upon at least partially filling the upper and the lowerinflatable rims 130 and 140 and the posterior frame 150, the devicedefines an open cavity 205 having an axial and a radial dimensions.

In another preferred embodiment, the present invention is a method ofmaking an intervertebral spinal fusion device comprising (a) insertingan inflatable device through a cannula into an intervertebral space; (b)orienting said inflatable device so that upon expansion a natural anglebetween two adjacent vertebrae will be at least partially restored; and(c) directing at least one member of the group consisting of aload-bearing component and an osteobiologic component into theinflatable device through the fluid communication means. Most preferablythe method of the present invention further includes the step ofhardening the load-bearing component. In one embodiment, said inflatabledevice includes an arcuate balloon connected to at least one fluidcommunication means, wherein said inflatable device upon expansionbetween two adjacent vertebrae has a footprint that substantiallycorresponds to a perimeter of a vertebral endplate and at leastpartially restores a natural angle between two adjacent vertebrae. Inanother embodiment, said inflatable device includes at least oneinflatable balloon, said device having an upper area, a lower area, ananterior area and a posterior area, and where upon expansion of theupper and the lower areas against the respective vertebral endplates,said anterior area is unequal to than said posterior area height, and afootprint of the device substantially corresponds to a rim of avertebral endplate. The at least one balloon can contain a plurality oflumena.

Preferably, the anterior area of the inflatable device is oriented toface an anterior aspect of a vertebra and the posterior area of thedevice is oriented to face a posterior aspect of the vertebra.

Most preferably, at least one of the load-bearing component and theosteobiologic component is directed into the balloon by directing atleast one component under pressure through the fluid communicationmeans, thereby causing the balloon to expand and directing the upperarea and the lower area of the device against the respective vertebralendplates, thereby at least partially restoring a natural angle betweentwo adjacent vertebrae.

In another preferred embodiment, at least a portion of the device usedto practice the method of the present invention, upon expansion, has agenerally toroidal shape thereby forming an open cavity defined by anouter surface of the toroidal shape having an axial dimension and aradial dimension. Preferably, the at least a portion of the device isoriented so that the axial dimension of the open cavity is substantiallyparallel to a major axis of a spinal column of a patient in which thedevice has been implanted.

In one embodiment, at least one of a load-bearing component and anosteobiologic component can be directed into the open cavity defined bythe expanded device.

The method of the present invention can further include the step ofdissolving at least one water-soluble material, thereby forming a porousmatrix.

Preferably, the method of the present invention further includes thestep of directing into the inflatable device osteoinductive and/orosteoconductive components.

In one preferred embodiment, the present invention is a method of atleast partially restoring a natural angle between two adjacent vertebraecomprising: (a) inserting an inflatable device through a cannula into anintervertebral space; (b) orienting said inflatable device so that uponexpansion a natural angle between two adjacent vertebrae will be atleast partially restored; and (c) expanding said inflatable device bydirecting at least one of a load-bearing component and an osteobiologiccomponent, into said inflatable device. The inflatable devices suitablefor practicing the method of the present invention are described above.

Preferably, the method of the present invention includes the step ofinflating said inflatable device. Inflating includes introducing atleast one of a load-bearing component and an osteobiologic componentinto said device by directing at least one component through the fluidcommunication means, thereby allowing the lower area and the upper areato engage the respective endplates and the anterior area height of saidinflatable device to be greater than the posterior area height, therebyat least partially restoring or creating a natural angle between twoadjacent vertebrae. Most preferably, the method further includes thestep of hardening at least one of the load-bearing component and anosteobiologic component.

In a preferred embodiment, the device upon expansion has a generallytoroidal shape thereby forming an open cavity defined by an outersurface of the toroidal shape and having an axial dimension and a radialdimension and the step of orienting said inflatable device includesorienting at least a portion of the device so that so that the axialdimension of the open cavity is substantially parallel to a major axisof a spinal column of a patient in which the device has been implanted.In one embodiment, the method further includes the step of introducingat least one of the load-bearing component and the osteobiologiccomponent into the cavity and the step of hardening at least one of theload-bearing component and an osteobiologic component. The method canfurther includes the step of dissolving at least one water-solublematerial, thereby forming a porous matrix.

The invention will now be further and specifically described by thefollowing examples that are not intended to be limiting in any way.

EXEMPLIFICATION Example 1 Employing a Method of the Present Invention

In performing a preferred method of the present invention, the patientis brought to the pre-surgical area and prepped. Anesthesia is theninduced and the area of the spine is further prepped. A small incisionthrough the muscles is opened under dissecting microscopicvisualization. The incision is made as small as possible and islongitudinal in the plane of the spine. The paravertebral muscles areseparated by blunt dissection and held apart with forceps and dividers.The intervertebral disc area is visualized, with initial exposure downto the lamina. The area below the lamina, at the point of theintervertebral foramina, can also be exposed.

The disc is examined for extruded material and any extruded material isremoved. Magnetic resonance imaging (“MRI”) data can be used todetermine the integrity of the annulus fibrosis at this point. Anarthroscope is inserted into the disc and used to examine the inside ofthe annulus. Optionally, an intraoperative discogram can be performed,in which a dye material is inserted and visualized in order tosubstantiate the integrity of the annulus fibrosis. Points of weakness,or rents, in the annulus fibrosis are identified and located andsuitable means, e.g., a bioabsorbable glue is employed to block theserents. If balloons are used to deliver all of the flowable materialsused in the present invention, then the rents need not be patched.

Distraction of the intervertebral disc space can then be accomplished,as described above, by inserting a deflated balloon into the disc spaceand delivering a fluid (preferably, the flowable load bearing componentof the present invention) into the balloon cavity.

Next, the endplates of the opposing vertebral body are partiallydecorticated, typically through the use of a curette, in order to allowblood flow into the disc space.

After endplate decortication, the application cannula is inserted intothe joint or disc space and under visualization from the fiberopticscope the biomaterial is delivered. The flow of the biomaterial iscontrolled by the operator via a foot pedal connected to the pumpingmechanism on the polymer canister. The biomaterial flows from the tip ofthe application catheter to fill the space provided.

If the load bearing component has a flowable component, the flowablecomponent is preferably solidified within 3 to 5 minutes, and preferablywithin 1 to 2 minutes. Once the disc space is suitably distracted, theosteobiologic component of the present invention is introduced to thedistracted space, thereby filling the remainder of the disc space. Thearthroscopic cannula and the application cannula are removed. Theflowable materials are further allowed to harden over 15 to 20 minutes.

The delivered biomaterial is allowed to cure, or cured by minimallyinvasive means and in such a manner that the cured biomaterial isretained in apposition to the prepared site. As described herein, thebiomaterial can be cured by any suitable means, either in a single stepor in stages as it is delivered. Once cured, the biomaterial surface canbe contoured as needed by other suitable, e.g., endoscopic orarthroscopic, instruments. The joint is irrigated and the instrumentsremoved from the portals.

At that point, interoperative x-rays are obtained to substantiate thepreservation of the intervertebral disc space. Direct observation of theintervertebral foramina for free cursing of the nerve rootlet issubstantiated by visualization. The retracted muscles are replaced andthe local fascia is closed with interrupted absorbable suture. Thesubcutaneous fascia and skin are then closed in the usual fashion. Thewound is then dressed.

Example 2 A Surgical Procedure that Employs Methods and Devices of thePresent Invention

A surgical procedure to fuse the vertebrae using methods and devices ofthe present invention can comprise the following steps:

-   -   i. Puncture or cut a flap in the annulus fibrosus and insert a        small diameter tube into the slit,    -   ii. Perform a conventional discectomy to remove the nucleus        pulposus,    -   iii. Insert a small diameter tube, e.g. a cannula, into the disc        space through the slit,    -   iv. Insert a strut, e.g. a balloon or a ramp having a partially        annular shape, into the disc space through the tube,    -   v. Flow glucose-containing polycaprolactone into the disc space        including the volume defined by the outer surface of the        partially annular balloon or a ramp, through the tube at about        70° C. Upon cooling to 37° C., the polycaprolactone should        become solid, thereby supplementing the mechanical attributes of        the strut,    -   vi. Leach out the glucose, thereby forming a porous matrix.    -   vii. Flow solutions laden with osteobiologic materials through        the porous matrix, so that the osteobiologic materials collect        in the pores. The tube can also have a vacuum port to collect        the eluted solution.    -   viii. remove the tube(s), seal the flap, and wait a month for        bone growth.

The result of this procedure is a formation of a fusion cage. Thisprocedure has numerous advantages. First, the resulting cage fills andsupports the entire disc space, and so it is stable and is not prone tosubsidence. Second, the minimally invasive treatment of the annulusfiborsus allows the resulting cage to be held in place by the retainedannulus fibrosus. Third, the in situ formation of a scaffold eliminatesthe need in high impaction forces. Four, by the very nature of aninflatable device, it is adjusted to fit the desired disc height.

Example 3 Harvesting Progenitor Cells for Use in Osteobiologic Material

Prior to performing spinal surgery, approximately 5 cc of bone marrow isaspirated from the iliac crest of the patient into a heparinized syringetube. The heparinized marrow is then passed through a selective cellattachment filter. The filter is designed for selective attachment ofosteoprogenitor cells such as mesenchymal stem cells and osteoblasts.Following selective cell attachment, the cells are tripsinized off ofthe filter and collected in a flask. The flask is then centrifuged toprecipitate a cell pellet on the bottom of the flask and the supernatantis poured off. The cells are then mixed with the injectable precursorform of the hydrogel. The precursor hydrogel is then poured into moldsthat are between 50-250 um in any dimension. The precursor hydrogel isthen cured, for example with a photoinitiator, to yield cell loadedhydrogel particles. These cell-hydrogel particles are then mixed withthe viscous form of the hardenable material and injected as theosteobiologic composition.

Example 4 Desirable Specifications for Lumbar Fusion Device

Specifications for lumbar interbody fusion devices are often formulatedassuming the following characteristics:

-   -   a) each vertebral endplate of a patient has a 1500 mm²        cross-sectional area,    -   b) the maximum in vivo load experienced by a patient is 3.4 kN;    -   c) the ultimate strength of a vertebral body is about 8.2 kN;    -   d) the device should initially be able resist the maximum in        vivo load;    -   e) after one year, the device should be able to resist half the        maximum in vivo load,    -   f) the strut portion of the device will have a footprint of 20        areal % of the disc space.

Accordingly, the following criteria for the device can be obtained:

Strength of a Load-Bearing Component

$\begin{matrix}{{{Ultimate}\mspace{14mu} {Strength}} = {\frac{8.2\mspace{14mu} {kN}}{300\mspace{14mu} {mm}^{2}} = {27\mspace{14mu} {MPa}}}} & (1) \\{{{Max}\mspace{14mu} {in}\mspace{14mu} {Vivo}\mspace{14mu} {Load}} = {\frac{3.4\mspace{14mu} {kN}}{300\mspace{14mu} {mm}^{2}} = {11.3\mspace{14mu} {MPa}}}} & (2)\end{matrix}$

Because both the strut and osteobiologic components will initially sharethe axial compressive load of the spine, the initial minimum strengthrequired by the device may be decreased. If the OB composition is chosento provide a 5 MPa strength and a 0.05 GPa modulus for at least 6-12weeks in order to mimic cancellous bone, then the OB composition mayshare about 10% of the applied compressive load when the modulus of thestrut is 2 GPa (assuming no annulus fibrosis). Therefore, the strengthof the strut may be about 10% lower.

Modulus of a Load-Bearing Component

It is preferred that the devices of the present invention have astiffness of at least 0.5 kN/mm. This lower preferred limit correspondsto the stiffness of conventional allograft cages. However, it isbelieved by some that the low stiffness of the allograft cages maysometime cause too much microfracture in the remodeling process.Therefore, in some embodiments, the stiffness of the devices of thepresent invention is preferably at least 5 kN/mm. Because it is believedthat excessive device stiffness may undesirably cause stress shieldingof the osteobiologic composition (and bone resorption), the stiffness ofthe device of the present invention is desirably no more than 50 kN/mm.

In many embodiments of the present invention, the stiffness of thedevice of the present invention is between 10 and 20 kN/mm. This rangeof values is comfortably between the range of stiffnesses found inconventional allograft cages (0.6-2.6 kN/mm) and CFRP cages (20-30kN/mm). Accordingly, it is believed that the devices of the presentinvention will have stiffness appropriate for the support of bony fusionthrough the disc space.

By way of non-limiting explanation, the stiffness of a component can becalculated as follows:

Comp. Modulus (GPa)×Area (mm²)/Disc Space Depth (mm)=Stiffness(kN/mm)  (7).

Assuming a disc space depth of 10 mm and area of 300 mm², the followingtable can be constructed:

TABLE I Intrinsic Material Device Compressive Modulus (GPa) Stiffness(kN/mm) 0.1 3 0.5 15 1.0 30 1.5 45

Because both the strut and osteobiologic components will initially sharethe axial compressive load of the spine, the initial minimum modulusrequired by the device may be decreased. If the OB composition is chosento provide a 5 MPa strength and a 0.05 GPa modulus for at least 6-12weeks in order to mimic cancellous bone, then the OB composition mayshare about 10% of the applied compressive load when the modulus of thestrut is 2 GPa (assuming no annulus fibrosis). Therefore, the modulus ofthe strut may be about 10% lower.

Similarly, if an initial device stiffness of 15 kN/mm is desired, thenthe strut stiffness should be about 1 GPa. As noted above, the materialreported by Timmer meets this requirement.

Example 5 Combinations of Materials and Devices

By way of introduction, the compositions and materials suitable for usein the present invention will be described below.

Exemplary compositions suitable for use as load-bearing component of thepresent invention that include a fumarate-based polymer (such aspolypropylene fumarate) cross-linked with a cross-linking agentcontaining a polypropylene fumarate-unit, such as polypropylenefumarate-diacrylate are disclosed in Timmer, Biomaterials (2003)24:571-577 (hereinafter, “Timmer”), the entire teachings of which areincorporated herein by reference. These compositions are characterizedby a high initial compressive strength (about 10-30 MPa) that typicallyincreases over the first 12 weeks, high resistance to hydrolyticdegradation (about 20-50 at 52 weeks), and an acceptable modulus for useas a strut (0.5-1.2 GPa).

Exemplary compositions suitable for use as resorbable cross-linkablecomponent comprises those cross-linkable components disclosed by Wise inU.S. Pat. No. 6,071,982 (hereinafter, “Wise”), the entire teaching ofwhich are herein incorporated by reference.

Exemplary absorbable elastomeric materials that allows resorbabledevices to be delivered through the cannula are disclosed in U.S. Pat.No. 6,113,624 by Bezwada (hereinafter, “Bezwada), the entire teachingsof which are incorporated herein by reference.

Exemplary injectable osteobiologic polymer-based compositions suitablefor use in the present invention are described in the U.S. Pat. No.5,679,723 by Cooper (herein after, “Cooper”), the entire teachings ofwhich are incorporated herein by reference.

Exemplary osteobiologic compositions in which porosity is produced insitu, are described in the U.S. Pat. No. 5,522,895 by Mikos(hereinafter, “Mikos”), the entire teachings of which are incorporatedherein by reference.

As used herein, “PCL” is polycaprolactone, “PLA” is poly(lactic acid),“PPF” is polypropylene fumarate and “PMMA” is polymethylmethacrylate.

As used herein, “IPN” or “interpenetrating networks” is a compositioncomprising two cross-linkable polymers, wherein two cross-linkablepolymers, upon exposure to appropriate cross-linking agents, cross-linkswith itself, but not with the other cross-linked polymer. “S-IPN” or“Semi-interpenetrating networks” is a composition comprising a firstcross-linkable polymer and a second non-cross-linkable polymer wherein,upon exposure to an appropriate cross-linking agent, the firstcross-linkable polymer cross-links with itself, while the second polymerremains unaffected.

According to Hao, Biomaterials (2003), 24:1531-39, (hereinafter, “Hao”)the entire teachings of which are incorporated herein by reference,certain mechanical properties of polycaprolactone increased by about 3fold when it was formed as a S-IPN. When at least 15 wt % HAP was added,the tensile modulus increased to 6 fold over conventionalpolycaprolactone.

Using the assumptions and criteria presented in Example 4, thecombinations of materials and devices of the present invention, providedbelow in Table II, were selected:

TABLE II LOAD-BEARING OSTEOBIOLOGIC Combi- Component Component nationComposition Balloon Composition Balloon 1. Timmer Short lived Wise-foamlock Bezwada PPF 2. PCL Short lived Cooper None 3. PCL S-IPN Short livedWise Bezwada 4. CaPO₄ Long lived CaPO₄ None 5. Wise PPF Long lived Mikosporogen None 6. PMMA- Permanent TBD TBD PCL 7. none none PLA beads Non-compliant 8. none none Timmer w/ Reinforced porogen stiff sidewalls

Combination 1

In this example, the Timmer IPN composition is chosen as the loadbearing composition in the strut because it has sufficient initial andlong term strength, acceptable modulus, and is resorbable.

Since the Timmer composition contains monomers, it is desirable tocontain the composition in an inflatable device during curing. Since theTimmer composition is relatively resistant to degradation, theinflatable device can be made of a resorbable material having a shorthalf life. Since the strut should also act as the distractor, theballoon should be non-compliant.

The Wise composition is chosen as the osteobiologic composition becauseis forms a scaffold having a strength and modulus essentially similar tothat of cancellous bone. It can be infiltrated in-situ with a hydrogelcontaining osteogenic cells and osteoinductive growth factors.

Since the Wise composition contains monomers, it is desirable to containthe composition in an inflatable device during curing. Since bonein-growth is desirable through the region occupied by the balloon, theinflatable device should be made of a resorbable material having a veryshort half life (such as one day). Since the Wise composition a 25%expansion during pore formation, it would be desirable for the balloonto be compliant to allow the Wise composition conform to the disc spacecontour.

Combination 2

In this example, solid neat polycaprolactone is chosen as the loadbearing composition in the strut because it has sufficient initialstrength (15 MPa), is very resistant to degradation, has an acceptablemodulus (0.5 GPa), and is resorbable.

Since solid polycaprolactone is relatively resistant to regradation, theinflatable device need not be relatively resistant to degradation, andso can be made of a resorbable material having a short half life. Sincethe strut should also act as the distractor, the balloon should benon-compliant.

The Cooper composition is chosen as the osteobiologic compositionbecause it is flowable at 40° C., and degrades sufficiently within a fewmonths to form an hydroxyapatite based-scaffold. Because of its lowdelivery temperature, certain dimer bone morphogenetic proteins can alsobe delivered during the injection of this composition.

Since the Cooper composition is fully biodegradable, there is no realneed to contain the composition in an inflatable device.

However, if it would be desirable to inject enough of the Coopercomposition to conform it to the disc space contour, then it may bedesirable to contain it in an inflatable device. Since bone in-growth isdesirable through the osteobiologic composition, the inflatable deviceshould be made of a resorbable material having a very short half-life(such as one day).

Combination 3

In this example, the polycaprolactone S-IPN composition (as reported inHao) is chosen as the load bearing composition in the strut because itmay have mechanical properties about 3-6 fold greater than neatpolycaprolactone, and is resorbable.

Since the polycaprolactone-polycaprolactone composition containsmonomers, it is desirable to contain the composition in an inflatabledevice during curing. Since the polycaprolactone composition isrelatively resistant to degradation, the inflatable device can be madeof a resorbable material having a short half life. Since the strutshould also act as the distractor, the balloon should be non-compliant.

Combination 4

In this example, CaPO₄ is chosen as the load bearing composition in thestrut because it has sufficient initial and long term strength,acceptable modulus, and is resorbable.

Since CaPO₄ is very susceptible to degradation, the inflatable deviceneed be relatively resistant to degradation, and so should be made of aresistant material that can contain the CaPO₄ for at least one year.Since the strut should also act as the distractor, the balloon should benon-compliant. One material that is resistant and non-compliant ispolyetherether ketone.

The CaPO₄ composition is chosen as the osteobiologic composition becauseit is flowable at body temperature, and degrades sufficiently within afew months to form an hydroxyapatite based-scaffold. Because of itsdelivery at body temperature, hydrogels containing temperature sensitiveadditives, such as osteogenic cells and osteoinductive components (suchas bone morphogenetic proteins), can also be delivered during theinjection of this composition.

Since the CaPO₄ composition is fully biodegradable, there is no realneed to contain the composition in an inflatable device.

Combination 5

In this example, the Wise composition is chosen as the load bearingcomposition in the strut because it has sufficient initial strength,acceptable modulus, and is resorbable.

Since the Wise composition is very susceptible to degradation, theinflatable device need be relatively resistant to degradation, and soshould be made of a resistant material that can contain the WiseComposition for at least one year. Since the strut should also act asthe distractor, the balloon should be non-compliant. One material thatis resistant and non-compliant is polyetherether ketone.

The Mikos composition is chosen as the osteobiologic composition becauseit is injectable at body temperature, forms an in-situ scaffold in whichhydrogels containing temperature sensitive additives, such as osteogeniccells and osteoinductive components (such as bone morphogeneticproteins), can be delivered.

Since a hydrogel should be injected into the Mikos composition duringsurgery, it is desirable to inject the Mikos composition without the aidof a balloon.

Combination 6

In this example, which is disclosed in Mendez, JBMR (2002), 61:66-74,the entire teachings of which are incorporated herein by reference,CaPO₄ is chosen as the load bearing composition in the strut because ithas sufficient initial and long term strength, acceptable modulus, andis resorbable.

Since CaPO₄ is very susceptible to degradation, the inflatable deviceneed be relatively resistant to degradation, and so should be made of aresistant material that can contain the CaPO₄ for at least one year.Since the strut should also act as the distractor, the balloon should benon-compliant. One material that is resistant and non-compliant ispolyetherether ketone.

Combination 7

The polylactic acid beads are chosen as the matrix of the osteobiologiccomposition because they can be packed into the disc space at bodytemperature and heat bonded with hot water to form an in-situ formedscaffold. If the beads are selected to have a 2 mm diameter, theporosity of the resulting scaffold will be about 40 vol % with a poresize of about 500 urn. Hydrogels containing temperature sensitiveadditives, such as osteogenic cells and osteoinductive components (suchas bone morphogenetic proteins), can then be delivered the in-situscaffold.

Since the packed beads must be packed into the disc space and then heatbonded with a high temperature fluid, it may be desirable to containboth the beads and the hot fluid in a balloon.

The Nitonol reinforced balloon is desirable because the reinforcementscan help the balloon withstand the high pressures needed during packing.

Since the polylactic acid beads have sufficient initial and long termstrength, acceptable modulus, there is no need for a strut.

Combination 8

Timmer polypropylene fumarate-polypropylene fumarate-diacrylate withtricalcium phosphate (Embodiment B) with 50 vol % porosity (or seededhydrogel phase) will still have a 25 MPa compressive strength after oneyear. If it takes the whole disc space, only 11.3 MPa is required. 2×safety factor.

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. (canceled)
 2. An intervertebral fusion device, comprising: a) firstand second structural walls; b) a core comprising first and second sidesurfaces connecting the walls, and an opening in the first side surface;and c) a cannula having a first end portion in fluid connection with theopening, wherein the walls are separated by a first distance W1 in acollapsed condition and a second distance W2 in an expanded condition,and wherein W2 is greater than W1.
 3. The device of claim 2, wherein thefirst and second structural walls and the first and second side surfacesdefine a cavity therebetween in the expanded condition, and furthercomprising: d) an osteobiologic graft material disposed in the cavity.4. The device of claim 2, wherein the device is arcuate.
 5. The deviceof claim 2, wherein the first and second structural walls are attachedto the core.
 6. The device of claim 2, wherein, in the expandedcondition, a height of the first side surface is less than a height ofthe second side surface.
 7. The device of claim 2, wherein, in theexpanded condition, a height of an anterior portion of the device isgreater than a height of a posterior portion of the device.
 8. Thedevice of claim 2, wherein, in the expanded condition, a height of ananterior portion of the device is less than a height of a posteriorportion of the device.
 9. The device of claim 2, wherein the structuralwalls allow bony fusion therethrough.
 10. The device of claim 2,wherein, in the expanded condition, a height of a medial portion of thedevice is greater than a height of lateral portions of the device. 11.The device of claim 2, wherein the core has openings sized to permitbony fusion therethrough.
 12. The device of claim 2, wherein thestructural walls have openings sized to permit bony fusion therethrough.13. A method of treating an intervertebral disc space between first andsecond opposed vertebral endplates, comprising: inserting into the discspace an intervertebral fusion device comprising: a) first and secondstructural walls, and b) a core comprising first and second sidesurfaces connecting the walls, and an opening in the first side surface,wherein the walls are separated by a first distance W1 in a collapsedcondition; expanding the device so that i) the walls are separated by asecond distance W2 in an expanded condition, wherein W2 is greater thanW1, and ii) the first and second structural walls and the first andsecond side surfaces define a cavity therebetween in the expandedcondition; and delivering osteobiologic graft material through theopening in the first side surface of the device and into the cavity. 14.The method of claim 13, wherein, in the expanded condition, the firstside surface has a height that is less than a height of the second sidesurface.
 15. The method of claim 13, wherein the delivering step isaccomplished by delivering the graft material through a cannula in fluidconnection with the opening.
 16. The method of claim 13, wherein, duringthe insertion step, the first structural wall opposes and is parallel tothe first vertebral endplate, and the second structural wall opposes andis parallel to the second vertebral endplate.
 17. The method of claim13, wherein the graft material is delivered after expanding the device.18. The method of claim 13, wherein expanding the device is effective torestore a natural angle between the first and second endplates.
 19. Themethod of claim 13, wherein expanding the device is effective todistract the first and second endplates.
 20. The method of claim 13,wherein inserting the device comprises positioning the device at ananterior periphery of the first and second endplates.
 21. The method ofclaim 13, wherein inserting the device comprises delivering the deviceto the disc space through a cannula.
 22. The method of claim 13, whereinthe graft material comprises autogenous bone graft.